Fused tricyclic compounds as inhibitors of tumor necrosis factor-alpha

ABSTRACT

Compounds of formula 1: 
     
       
         
         
             
             
         
       
     
     are disclosed, wherein V is CH 2 ; W is S(O) m ; m is the integer 0, 1 or 2; U is O, C(O), CR 13 R 14  or NR 15 ; where R 13  is H, alkyl; R 14  is H, OH, OR 13  or OCOR 13 ; R 15  is H, alkyl, cycloalkyl, alkenyl, C(O)R 13 , C(O)OR 13  or alkylaminocarbonyl; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 5  are as defined herein. These compounds are inhibitors of tumor necrosis factor-alpha (TNF-α) and are useful as medicaments for the treatment and prevention of disorders caused by increased TNF-α activity, in particular inflammations.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is related to our copending patent applicationentitled: ‘Tricyclic guanidine derivatives as sodium-proton exchangeinhibitors’, filed on the same date as the present application.

FIELD OF THE INVENTION

The present invention relates to novel condensed tricyclic compounds,which are inhibitors of Tumor Necrosis Factor-alpha (TNF-α), toprocesses for their preparation, pharmaceutical compositions containingthem and their use in medicines for treatment and prevention ofdisorders caused by increased TNF-αactivity, such as inflammations.

BACKGROUND OF THE INVENTION

Tumor Necrosis Factor-α (TNF-α), a pleiotropic cytokine, is producedmainly by macrophages, but other types of cells also produce it. TNF-αdemonstrates beneficial as well as pathological activities. It has bothgrowth stimulating effects and growth inhibitory properties, besidesbeing self-regulatory. The beneficial functions of TNF-α includemaintaining homeostasis by regulating the body's circadian rhythm,mounting an immune response to bacterial, viral, fungal and parasiticinfections, replacing or remodeling injured tissue by stimulatingfibroblast growth and, as the name suggests, killing certain tumors.TNF-α has been implicated as a mediator in inflammatory bowel disease,inflammation, rheumatoid arthritis, juvenile rheumatoid arthritis,psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis,chronic non-rheumatoid arthritis, osteoporosis/bone resorption, Crohn'sdisease, septic shock, endotoxic shock, atherosclerosis,ischemia-reperfusion injury, coronary heart disease, vasculitis,amyloidosis, multiple sclerosis, sepsis, chronic recurrent uveitis,hepatitis C virus infection, malaria, ulcerative colitis, cachexia,psoriasis, plasmocytoma, endometriosis, Behcet's disease, Wegenrer'sgranulomatosis, AIDS, HIV infection, autoimmune disease, immunedeficiency, common variable immunodeficiency (CVID), chronicgraft-versus-host disease, trauma and transplant rejection, adultrespiratory distress syndrome, pulmonary fibrosis, recurrent ovariancancer, lymphoproliferative disease, refractory multiple myeloma,myeloproliferative disorder, diabetes, juvenile diabetes, meningitis,ankylosing spondylitis, skin delayed type hypersensitivity disorders,Alzheimer's disease, systemic lupus erythematosus and allergic asthma.Much research has been conducted to study the effect of TNF-α andanti-TNF-α therapies. Studies in the area of cancer have shown that withTNF-α therapy it is important to balance the cytotoxicity and systemictoxicity of the potential drug candidates.

Inflammation is the response of a tissue to injury that may be caused byinvading parasites, ischemia, antigen-antibody reactions or other formsof physical or chemical injury. It is characterized by increased bloodflow to the tissue, causing pyrexia, redness, swelling, and pain. Eachstimulus elicits a characteristic response that has a common theme.Inflammation occurs in three distinct phases:

-   -   1. an acute transient phase characterized by local vasodilation        and increased capillary permeability;    -   2. a subacute phase characterized by infiltration of the site by        leucocytes and phagocytic cells; and    -   3. a chronic proliferative phase characterized by tissue        degeneration and fibrosis. The recruitment of inflammatory cells        to sites of injury involves the concerted interactions of        several types of mediators.

Several cytokines, especially IL-1 (interleukin-1) and TNF-α (tumornecrosis factor-α), play an important role in the inflammatory process.Both IL-1 and TNF-α are derived from mononuclear cells and macrophagesand in turn induce the expression of a variety of genes that contributeto the inflammatory process. An increase in TNF-α synthesis/release is acommon phenomenon during the inflammatory process. Inflammation is aninherent part of various disease states like rheumatoid arthritis,Crohn's disease, septic shock syndrome, atherosclerosis, among otherclinical conditions.

Rheumatoid arthritis (RA)—an autoimmune disorder, is a chronic,systemic, articular inflammatory disease of unknown etiology. In RA, thenormally thin synovial lining of joints is replaced by an inflammatory,highly vascularized, invasive fibrocollagenase tissue (pannus), which isdestructive to both cartilage and bone. Areas that may be affectedinclude the joints of the hands, wrists, neck, jaw, elbows, feet andankles. Cartilage destruction in RA is linked to aberrant cytokines andgrowth factor expression in the affected joints.

The most common rheumatoid arthritis therapy involves the use ofnonsteroidal anti-inflammatory drugs (NSAIDs) to alleviate symptoms.However, despite the widespread use of NSAIDs, many individuals cannottolerate the doses necessary to treat the disorder over a prolongedperiod of time. In addition, NSAIDs merely treat the symptoms ofdisorder and not the cause.

When patients fail to respond to NSAIDs, other drugs such asmethotrexate, gold salts, D-penicillamine and prednisone are used. Thesedrugs also have significant toxicities and their mechanism of actionremains unknown. TNF-α is considered to be at the apex of theproinflammatory cytokine cascade. Elevated circulating TNF-α levels andexpression of other proinflammatory mediators are diminished byanti-TNF-α treatment, indicating possible beneficial effects thistreatment can offer. Intervention of TNF-α activity can occur at thesynthesis, release and receptor levels. Anti-TNF-α monoclonalantibodies, soluble receptors or receptor fusion proteins will targetthe TNF-αreceptors/binding. Synthesis of TNF-α can also be suppressed bydrugs/agents such as cyclosporine A, glucocorticoids or interleukin-10.

There are several small molecules, which inhibit the production ofinflammatory cytokines and have demonstrated activity in animalrheumatoid arthritis models. Potential advantages of small molecules arethat they are convenient to use for chronic problems, might facilitatetissue penetration, can be used in combination with otheranti-inflammatory therapies. Such molecules are in various stages ofpreclinical and clinical development (Nature Reviews, 2003, 2, 736-746).

US 2003/0171585 describes tricyclic compounds (triphenylpropanamides) asanti-inflammatory agents.

JP 08-119920 describes tricyclic compounds (anilide derivatives) assteroid 5α-reductase inhibitors useful in the treatment of prostatecancer, baldness and syphilis.

JP 11-130772 describes nitrogen-containing tricyclic compounds asleukocyte activation inhibitors that are useful for the treatment ofinflammatory and allergic diseases.

JP 90-40662 describes tricyclic compounds that are substance P andbradykinin antagonists and are useful for the treatment of manydiseases, including inflammation.

J. Med. Chem., 1970, Vol. 13, no. 4, 713-722, describes derivatives of 511-dihydrodibenz[b,e][1,4]oxazepine showing anti-anxiety and CNSdepressant activities.

Monoclonal antibody drugs such as Infliximab, Etanercept and Adalimumabare useful as anti-inflammatory agents, but have drawbacks such as routeof administration (only parenteral), high cost, allergy induction,activation of latent tuberculosis, increased risk of cancer andcongestive heart disease. There is a need for improved and alternativemedicaments for the prevention and treatment of inflammatory disorderscaused by increased TNF-α activity.

SUMMARY OF THE INVENTION

The present invention relates to novel condensed tricyclic compounds ofgeneral formula 1 or 1′ (as provided herein below), as well as prodrugs,tautomeric forms, stereoisomers, pharmaceutically acceptable salts orsolvates or polymorphs thereof, which inhibit TNF-α activity. Thecompounds of general formula 1 or 1′ are useful for the treatment andprevention of diseases caused by increased TNF-α activity, such asrheumatoid arthritis, Crohn's disease, septic shock syndrome andatherosclerosis.

The present invention also relates to the subject condensed tricycliccompounds, which inhibit interleukin (IL-1, IL-6, IL-8) activity. Thecompounds are useful for the treatment and prevention of diseases causedby increased interleukin (IL-1, IL-6, IL-8) activity such as rheumatoidarthritis, osteoarthritis and other autoimmune conditions.

The invention further relates to pharmaceutical compositions comprisingthe subject condensed tricyclic compounds as active ingredient for themedical conditions caused by increased TNF-α activity indicated herein,especially inflammatory disorders.

The invention still further relates to processes for producing thesubject condensed tricyclic compounds of general formula 1 or 1′.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel tricyclic compounds represented bythe following general formula 1:

whereinR₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are each independently selected from:hydrogen, halogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, cyano,nitro, trifluoromethyl, aryl, heterocyclyl, heteroaryl, alkyl sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, sulfonamide, —S(O)₂—NH-alkyl,—S(O)₂—NH-cycloalkyl, —S(O)₂—NH-heterocyclyl, —S(O)₂—NH-heteroaryl,—S(O)₂—NH-aryl, —NH—S(O)₂-alkyl, —NH—S(O)₂-cycloalkyl, —NH—S(O)₂-aryl,—NH—S(O)₂-heterocyclyl, —NH—S(O)₂-heteroaryl, —(CH₂)_(n)C(O)R₉,—C(O)NR₁₁R₁₂, —NR₁₁R₁₂, hydrazine and N═R′;n is the integer 0, 1 or 2;R₉ is hydrogen, halogen, alkyl, cycloalkyl, aralkyl, trifluoromethyl,OR₁₀, aryl or heterocyclyl;R₁₀ is hydrogen, alkyl, cycloalkyl, trifluoromethyl, aryl orheterocyclyl;R₁₁ and R₁₂ are each independently selected from: hydrogen, alkyl,cycloalkyl, alkoxyl, aryl, heterocyclyl, heteroaryl, —(CH₂)_(n)C(O)R₉,alkylamino and cycloalkylaminocarbonyl; or R₁₁ and R₁₂, together withthe N atom to which they are bonded, form a 5-, 6-, 7- or 8-memberedheterocyclyl, optionally having one or more additional heteroatomsselected from: O, N and S;R′ is heterocyclyl or cycloalkyl;where alkyl or cycloalkyl is unsubstituted or substituted by one or twoof the same or different groups selected from: halogen, hydroxy,carboxy, acetoxy, amino, cycloalkyl, alkoxy, aryloxy, alkoxy carbonyl,amino carbonyl, alkylamino, dialkylamino, cycloalkylamino,cycloalkylalkylamino, heterocyclylalkylamino, heteroarylamino,heteroarylalkylamino, dialkylaminoalkylamino, aminoaryl, aryl,heteroaryl and heterocyclyl;heterocyclyl is unsubstituted or substituted by one or two of the sameor different groups selected from: halogen, hydroxy, alkoxy, oxo, alkyl,cycloalkyl, cycloalkylalkyl, amino, aminoalkyl, hydroxyalkyl,heterocyclylalkyl, heteroarylalkyl, aralkyl, alkylaminoalkyl, formyl,alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl,arylcarbonyl, heteroarylcarbonyl, —SH, —S-alkyl, —S(O)₂-alkyl,—S(O)₂-aryl, aryl, alkylheteroaryl, cycloalkylheteroaryl, alkylamino andalkylheteroarylamino;aryl is unsubstituted or substituted by one or two of the same ordifferent groups selected from: halogen, nitro, alkyl, trifluoromethyl,alkoxy, amino, mono- or di-alkylamino, heteroarylalkyl and aralkyl;heteroaryl is unsubstituted or substituted by one or two of the same ordifferent groups selected from: halogen, alkyl, cycloalkyl, nitro andamino;

U is O; V is CH₂, CHCH₃ or C(CH₃)₂ or NH; W is S(O)_(m); and

m is the integer 0, 1 or 2;in all its stereoisomeric and tautomeric forms and mixtures thereof inall ratios, and its pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates, pharmaceutically acceptable polymorphs andprodrugs.

The present invention also provides novel tricyclic compoundsrepresented by the following general formula 1′:

whereinR₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are each independently selected from:hydrogen, halogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, cyano,nitro, trifluoromethyl, aryl, heterocyclyl, heteroaryl, alkyl sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, sulfonamide, —S(O)₂—NH-alkyl,—S(O)₂—NH-cycloalkyl, —S(O)₂—NH-heterocyclyl, —S(O)₂—NH-heteroaryl,—S(O)₂—NH-aryl, —NH—S(O)₂-alkyl, —NH—S(O)₂-cycloalkyl, —NH—S(O)₂-aryl,—NH—S(O)₂-heterocyclyl, —NH—S(O)₂-heteroaryl, —(CH₂)_(n)C(O)R₉,—C(O)NR₁₁R₁₂, —NR₁₁R₁₂, hydrazine and N═R′;n is the integer 0, 1 or 2;R₉ is hydrogen, halogen, alkyl, cycloalkyl, aralkyl, trifluoromethyl,aralkyl, OR₁₀, aryl or heterocyclyl;R₁₀ is hydrogen, alkyl, cycloalkyl, trifluoromethyl, aralkyl, aryl orheterocyclyl;R₁₁ and R₁₂ are each independently selected from: hydrogen, alkyl,cycloalkyl, alkoxy, aryl, heterocyclyl, heteroaryl, —(CH₂)_(n)C(O)R₉,alkylamino and cycloalkylaminocarbonyl; or R₁₁ and R₁₂, together withthe N atom to which they are bonded, form a 5-, 6-, 7- or 8-memberedheterocyclyl, optionally having one or more additional heteroatomsselected from: O, N and S;R′ is selected from: heterocyclyl and cycloalkyl;

U is C(O), CR₁₃R₁₄ or NR₁₅;

R₁₃ is H, alkyl, cycloalkyl or alkenyl;

R₁₄ is H, OH, OR₁₃ or OCOR₁₃;

R₁₅ is H, alkyl, cycloalkyl, alkenyl, C(O)R₁₃, C(O)OR₁₃ oralkylaminocarbonyl;where alkyl or cycloalkyl is unsubstituted or substituted by one or twoof the same or different groups selected from: halogen, hydroxy,carboxy, acetoxy, amino, cycloalkyl, alkoxy, aryloxy, alkoxy carbonyl,amino carbonyl, alkylamino, dialkylamino, cycloalkylamino,cycloalkylalkylamino, heterocyclylalkylamino, heteroarylamino,heteroarylalkylamino, dialkylaminoalkylamino, aminoaryl, aryl,heteroaryl and heterocyclyl;heterocyclyl is unsubstituted or substituted by one or two of the sameor different groups selected from: halogen, hydroxy, alkoxy, oxo, alkyl,cycloalkyl, cycloalkylalkyl, amino, aminoalkyl, hydroxyalkyl,heterocyclylalkyl, heteroarylalkyl, aralkyl, alkylaminoalkyl, formyl,alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl,arylcarbonyl, heteroarylcarbonyl, —SH, —S-alkyl, —S(O)₂-alkyl,—S(O)₂-aryl, aryl, alkylheteroaryl, cycloalkylheteroaryl, alkylamino andalkylheteroarylamino;aryl is unsubstituted or substituted by one or two of the same ordifferent groups selected from: halogen, nitro, alkyl, trifluoromethyl,alkoxy, amino, mono- or di-alkylamino, heteroarylalkyl and aralkyl;heteroaryl is unsubstituted or substituted by one or two of the same ordifferent groups selected from: halogen, alkyl, cycloalkyl, nitro andamino;

V is CH₂, CHCH₃ or C(CH₃)₂ or NH; W is S(O)_(m); and

m is the integer 0, 1 or 2;with the provisos that

-   -   (i) when R₁, R₂, R₃, R₄, R₅, R₆, R₇ or R₈ is C(O)NR₁₁R₁₂, then        R₁₁ or R₁₂ is other than alkyl substituted by heteroaryl; and    -   (ii) when R₁, R₂, R₃, R₄, R₅, R₆, R₇ or R₈ is C(O)NR₁₁R₁₂, where        one of R₁₁ and R₁₂ is H or alkyl and the other is substituted        aryl, then W is S(O)_(m) wherein m is the integer 1 or 2; and    -   (iii) when U is NR₁₅, where R₁₅ is H or substituted alkyl, then        at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇ or R₈ is C(O)R₉ or        C(O)NR₁₁R₁₂, and    -   (iv) when U is CR₁₃R₁₄, where R₁₃ is alkyl substituted by        —NH-alkylaryl or by hydroxyl or is alkenyl and R₁₄ is hydrogen        or alkoxy, then W is S(O)_(m) wherein m is the integer 1 or 2;    -   (v) when U is C(O), then W is S(O)_(m) wherein m is the integer        1 or 2;        in all its stereoisomeric and tautomeric forms and mixtures        thereof in all ratios, and its pharmaceutically acceptable        salts, pharmaceutically acceptable solvates, pharmaceutically        acceptable polymorphs and prodrugs.

Listed below are definitions which apply to the terms as they are usedthroughout the specification and the appended claims (unless they areotherwise limited in specific instances), either individually or as partof a larger group.

These broad or preferred definitions apply both to the end products ofthe formula (1) or (1′) (above) and formula (1a) or (1a′) (as providedherein below) and, correspondingly, to the starting materials andintermediates required in each case for the preparation. Thesedefinitions should not be interpreted in the literal sense as they arenot general definitions and are relevant only for this application.

As used herein, the term “alkyl” whether used alone or as part of asubstituent group, refers to the radical of saturated aliphatic groups,including straight or branched-chain alkyl groups. Furthermore, unlessstated otherwise, the term “alkyl” includes unsubstituted alkyl groupsas well as alkyl groups, which are substituted by one or more differentsubstituents. In preferred embodiments, a straight chain or branchedchain alkyl has 20 or fewer carbon atoms in its backbone (e.g., C₁-C₂₀for straight chain, C₃-C₂₀ for branched chain), and more preferably 15or fewer carbon atoms. Examples of alkyl residues containing from 1 to20 carbon atoms are: methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl,octadecyl and eicosyl, the n-isomers of all these residues, isopropyl,isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl,2-methylpentyl, 3-methylpentyl, isohexyl, 2,3,4-trimethylhexyl,isodecyl, sec-butyl, or tert-butyl. Preferred examples of alkyl residuecontain from 1 to 6 carbon atoms, more preferably from 1 to 4 carbonatoms such as methyl, ethyl, propyl, isopropyl, n-propyl, t-butyl,n-butyl, sec-butyl and iso-butyl.

The term “cycloalkyl” refers to a saturated mono-, bi- or poly-cyclicring system containing a specified number of carbon atoms. Preferredcycloalkyls have from 3-10 carbon atoms in their ring structure, andmore preferably have 3, 4, 5, 6 or 7 carbon atoms in the ring structure.Examples of cycloalkyl residues containing 3, 4, 5, 6 or 7 ring carbonatoms are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl. Furthermore, unless stated otherwise, the term ‘cycloalkyl’includes unsubstituted cycloalkyl and cycloalkyl which is substituted byone or more identical or different groups selected from any substitutionmentioned below for alkyl, including alkyl, alkenyl, aminoalkyl,carbonyl-substituted alkyl, fluoroalkyls such as —CF₃ and the like.Cycloalkyl groups comprise saturated cycloalkyl ring systems which donot contain any double bonds within the rings as well as partiallyunsaturated cycloalkyl ring systems which contain one or more,preferably one, two or three, double bonds within the rings providedthat the resulting system is stable and the double bonds are not locatedin such a manner that an aromatic system results.

Unless stated otherwise, and irrespective of any specific substituentsbonded to alkyl groups that are indicated in the definition of thecompounds of the formula (1) or (1′) (above) and formula (1a) or (1a′)(below), alkyl groups can in general be unsubstituted or substituted byone or more (for example 1, 2, 3, 4 or 5) identical or differentsubstituents. Any kind of substituent present in substituted alkylresidues can be present in any desired position provided that thesubstitution does not lead to an unstable molecule. A substituted alkylrefers to an alkyl residue in which one or more, for example, 1, 2, 3, 4or 5 hydrogen atoms are replaced with substituents, for example,halogen, hydroxyl, carbonyl, alkoxyl, cycloalkyl, ester, ether, cyano,amino, amido, imino, sulfhydryl, alkylthio, thioester, sulfonyl, nitro,azido, acyloxy, heterocyclo, aralkyl, or an aryl or heteroaryl group.The carbon backbone of the alkyl group may contain heteroatoms such asoxygen, sulfur or nitrogen. Examples of substituted acyclic alkyls arehydroxymethyl, hydroxyethyl, 2-hydroxyethyl, aminoethyl ormorpholinoethyl.

It will be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate. For example, the substituents of a substituted alkyl mayinclude substituted and unsubstituted forms of amino, imino, amido,sulfonyl (including sulfonate and sulfonamide), as well as ether,alkylthio, carbonyl (including ketones, aldehydes, carboxylates, andesters), fluoroalkyls such as —CF₃, cyano and the like.

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double or triple bond,respectively, for example 1, 2 or 3 double bonds and/or triple bonds,provided that the double bonds are not located within a cyclic alkylgroup in such a manner that an aromatic system results. Examples ofalkenyl groups include vinyl, 1-propenyl, 2-propenyl, 2-butenyl,2-methyl-1-propenyl, 3-methyl-2-butenyl etc. Examples of alkynyl groupsinclude ethynyl, 2-propynyl, 2-butynyl and 3-butynyl.

Furthermore, unless otherwise stated, the terms “alkenyl” and “alkynyl”include unsubstituted alkenyl and alkynyl groups as well as alkenyl andalkynyl groups which are substituted by one or more (for example 1, 2,3, 4 or 5), identical or different groups mentioned above for alkyl, forexample, aminoalkenyl, aminoalkynyl, amidoalkenyl, amidoalkynyl,iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl,carbonyl-substituted alkenyl or alkynyl, alkenoxyl or alkynoxyl.

As used herein the term “alkoxyl” or “alkoxy” refers to an alkyl grouphaving an oxygen radical attached thereto, wherein alkyl is as definedabove. The terms include, therefore, alkoxyl or alkoxy groups which aresubstituted by one or more identical or different groups mentioned abovefor alkyl. Representative alkoxyl groups include methoxy, ethoxy,propoxy, tert-butoxy and the like.

As used herein the term “acyl” refers to any group or organic radicalsuch as alkyl (which can be further substituted with an alkyl, alkoxy,cycloalkylamino, hydroxy or halo) or cycloalkyl attached to a carbonylgroup, wherein alkyl and cycloalkyl are as defined above.

As used herein the term “aryl” refers to a monocyclic or polycyclichydrocarbon group having up to 14 ring carbon atoms, preferably up to 10ring carbon atoms, in which at least one carbocyclic ring is presentthat has a conjugated π electron system. Suitable examples of(C₆-C₁₄)-aryl residues include phenyl, naphthyl, biphenyl, fluorenyl oranthracenyl, especially phenyl and naphthyl. Unless stated otherwise,and irrespective of any specific substituents bonded to aryl groupswhich are indicated in the definition of the compounds of formula (1) or(1′) (above) and formula (1a) or (1a′) (below), aryl residues, forexample phenyl, naphthyl or fluorenyl, can in general be optionallysubstituted by one or more substituents, preferably by up to fiveidentical or different substituents selected from the groups consistingof halogen, alkyl, alkenyl, alkynyl, fluoroalkyl such as CF₃, hydroxyl,aryloxy, amino, substituted amino, cyano, nitro, thiol, imine, amide,carbonyl (such as carboxyl, formate, carbamide, ester, ketone oraldehyde), sulfhydryl, alkylthio, silyl ether, thiocarbonyl (such asthioester, thioacetate or thioformate), sulfonyl, aminoacid ester and aheterocyclo group, which is saturated, partially unsaturated oraromatic. Aryl residues can be bonded via any desired position, and insubstituted aryl residues the substituents can be located in any desiredposition. For example, in monosubstituted phenyl residues thesubstituent can be located in the 2-position, the 3-position, the4-position or the 5-position. If the phenyl group carries twosubstituents, they can be located in 2,3-position, 2,4-position,2,5-position, 2,6-position, 3,4-position or 3,5-position.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen andsulfur. It should be noted that any heteroatom with unsatisfied valencesis assumed to have a hydrogen atom to satisfy the valences.

The terms “heterocyclyl”, “heterocycle” and “heterocyclo” refer to asaturated, partially unsaturated or aromatic monocyclic or polycyclicheterocyclic ring system containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13or 14 ring atoms of which 1, 2, 3 or 4 are identical or differentheteroatoms selected from: nitrogen, oxygen and sulfur. The heterocyclylgroup may, for example, have 1 or 2 oxygen atoms and/or 1 or 2 sulfuratoms and/or 1 to 4 nitrogen atoms in the ring. In monocyclic groups,heterocyclyl preferably is a 3-membered, 4-membered, 5-membered,6-membered or 7-membered ring, more preferably a 5- or 6-membered ring.Suitable examples of such heterocyclyl groups are piperazinyl,piperidinyl imidazolyl, pyrrolidinyl and morpholinyl. In polycyclicgroups, heterocyclyl may comprise either fused rings in which two ormore carbons are common to two adjoining rings, or bridged rings inwhich rings are joined through non-adjacent atoms. In polycyclic groups,heterocyclyl preferably comprises two fused rings (bicyclic), one ofwhich is a 5- or 6-membered heterocyclic ring and the other of which isa 5- or 6-membered heterocyclic ring. Exemplary bicyclic and tricyclicheterocyclic groups include benzoxazolyl, quinolyl, isoquinolyl,carbazolyl, indolyl, isoindolyl, phenoxazinyl, benzothiazolyl,benzimidazolyl, benzoxadiazolyl and benzofurazanyl.

The ring heteroatoms can be present in any desired number and in anyposition with respect to each other provided that the resultingheterocyclic system is known in the art and is stable and suitable as asubgroup in a drug substance. Preferred are heterocyclyl groups having 1or 2 identical or different heteroatoms selected from: nitrogen, oxygenand sulfur. Examples of such heterocyclyl groups are: pyrrolyl, furyl,thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,azepinyl, tetrahydrothiophenyl, tetrahydrofuranyl, morpholinyl,thiomorpholinyl, tetrahydropyranyl, lactams, pyrrolidinyl, azetidinyl,piperidinyl, piperazinyl and the like.

The heterocyclyl group may be bonded via any ring carbon atom, and inthe case of nitrogen heterocycles via any suitable ring nitrogen atom.Thus, for example, a pyrrolyl residue can be 1-pyrrolyl, 2-pyrrolyl or3-pyrrolyl, a pyrrolidinyl residue can be 1-pyrrolidinyl (=pyrrolidino),2-pyrrolidinyl or 3-pyrrolidinyl, and imidazolyl can be 1-imidazolyl,2-imidazolyl, 4-imidazolyl or 5-imidazolyl.

Heterocyclyl comprises saturated heterocyclic ring systems which do notcontain any double bonds within the rings, as well as unsaturatedheterocyclic ring systems which contain one or more, preferably up to 5double bonds within the rings provided that the resulting system isstable. Unsaturated rings may be non-aromatic or aromatic. Aromaticheterocyclyl groups may also be referred to by the customary term“heteroaryl” for which all the definitions and explanations above andbelow relating to heterocyclyl apply.

Unless stated otherwise, and irrespective of any substituents bonded toheterocyclyl groups which are indicated in the definition of thecompounds of formula (1) or (1′) (above) and formula (1a) or (1a′)(below), the heterocyclyl group can be unsubstituted or substituted onring carbon atoms with one or more substituents, preferably up to fiveidentical or different substituents. Each suitable ring nitrogen atom ina heterocyclyl group can independently of the other be unsubstituted,i.e. carry a hydrogen atom, or can be substituted. Suitable examples ofsubstituents for the ring carbon and ring nitrogen atoms are:(C₁-C₈)-alkyl, in particular (C₁-C₄)-alkyl, alkoxy, halogen, hydroxyl,hydroxy-(C₁-C₄)-alkyl such as, for example, hydroxymethyl or1-hydroxyethyl or 2-hydroxyethyl, alkenyl, alkynyl, fluoroalkyl such asCF₃, aryloxy, amino, cyano, nitro, thiol, imine, amide or carbonyl (suchas carboxyl, formate, carbamide, an ester, ketone or aldehyde), silylether, thiocarbonyl (such as thioesters, a thioacetate or athioformate), sulfonyl, aminoacid ester, heterocyclyl, aryl or the like.The substituents can be present at one or more positions provided that astable molecule results.

As used herein the term “aralkyl” refers to an alkyl group substitutedwith an aryl or heteroaryl group, wherein the terms alkyl, aryl andheteroaryl are as defined above. Exemplary aralkyl groups include—(CH₂)_(p)-phenyl, —(CH₂)_(p)-pyridyl, —(CH₂)_(p)-imidazolyl,—(CH₂)_(p)-thiophenyl and —(CH₂)_(p)-furyl, wherein p is an integer from1 to 3.

The term “halogen” refers to fluorine, chlorine, bromine or iodine,preferably fluorine, chlorine or bromine.

As used herein the terms, mono- or di-substituted amino refers to anamino group substituted by one or two groups which may be the same ordifferent. For instance, mono-substituted amino means an amino group inwhich only one hydrogen atom is replaced with a substituent.Disubstituted amino means an amino group in which both the hydrogenatoms are replaced with the same or different substituents. Thesubstituents on the amino group are independently selected from: alkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, acyl, haloacyl, heterocyclylalkyl,heteroaryalkyl, aminoalkyl, alkoxyaralkyl and the like. It will beunderstood by those skilled in the art that the moieties on the aminogroup can themselves be substituted, if appropriate.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, as wellas represents a stable compound, which does not readily undergotransformation such as by rearrangement, cyclization, elimination, etc.

In one embodiment, the present invention provides novel tricycliccompounds represented by the formula 1 above, wherein R₇ is alkyl,—(CH₂)_(n)C(O)R₉ or —C(O)NR₁₁R₁₂; where n, R₉, R₁₀, R₁₁ and R₁₂ are asdefined above.

In another embodiment, the present invention provides novel tricycliccompounds represented by the formula 1′ above, wherein R₇ is alkyl,—(CH₂)_(n)C(O)R₉ or —C(O)NR₁₁R₁₂; where n, R₉, R₁₀, R₁₁ and R₁₂ are asdefined above; and with the provisos that

-   (i) when R₇ is C(O)NR₁₁R₁₂, then R₁₁ or R₁₂ is other than alkyl    substituted by heteroaryl; and-   (ii) when R₇ is C(O)NR₁₁R₁₂, where one of R₁₁ and R₁₂ is H or alkyl    and the other is substituted aryl, then W is S(O)_(m), wherein m is    the integer 1 or 2, and-   (iii) when U is CR₁₃R₁₄, where R₁₃ or R₁₄ is alkyl substituted by    —NH-alkylaryl, or by hydroxyl or is alkenyl and R₁₄ is hydrogen or    alkoxy, then W is S(O)_(m), wherein m is the integer 1 or 2;-   (iv) when U is C(O), then W is S(O)_(m) wherein m is the integer 1    or 2;    in all its stereoisomeric and tautomeric forms and mixtures thereof    in all ratios, and its pharmaceutically acceptable salts,    pharmaceutically acceptable solvates, pharmaceutically acceptable    polymorphs and prodrugs.

In another embodiment, the present invention provides novel tricycliccompounds represented by the following formula 1a:

whereinR₁, R₂, R₃, R₄, R₅, R₆ and R₅ are each independently selected from:hydrogen, halogen, hydroxy, alkyl, alkenyl, cycloalkyl, alkoxy, cyano,nitro, trifluoromethyl, aryl, heterocyclyl, heteroaryl, alkylsulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, —S(O)₂—NH-heterocyclyl,—S(O)₂—NH-heteroaryl, sulfonamide, —S(O)₂—NH-alkyl,—S(O)₂—NH-cycloalkyl, —S(O)₂—NH-aryl, —NH—S(O)₂-alkyl,—NH—S(O)₂-cycloalkyl, —NH—S(O)₂-aryl, —NH—S(O)₂-heterocyclyl,—NH—S(O)₂-heteroaryl, —(CH₂)_(n)C(O)R₉, NR₁₁R₁₂, hydrazine and N═R′;R₇ is alkyl, —(CH₂)_(n)C(O)R₉ or —C(O)NR₁₁R₁₂;R₉ is hydrogen, halogen, alkyl, cycloalkyl, trifluoromethyl, OR₁₀, arylor heterocyclyl;R₁₀ is hydrogen, alkyl, cycloalkyl, trifluoromethyl, aryl orheterocyclyl;R₁₁ and R₁₂ are each independently selected from: hydrogen, alkyl,cycloalkyl, alkylamino, aryl, heteroaryl, heterocyclyl, —(CH₂)_(n)C(O)R₉and cycloalkylaminoalkylcarbonyl; or R₁₁ and R₁₂, together with the Natom to which they are bonded, form a 5-, 6-, 7- or 8-memberedheterocyclyl, optionally having one or more additional heteroatomsselected from: O, N and S;R′ is heterocyclyl or cycloalkyl;n is the integer 0, 1 or 2;where alkyl or cycloalkyl is unsubstituted or substituted by one or twoof the same or different groups selected from: halogen, hydroxy,alkylcarboxy, amino, cycloalkyl, alkoxy, aryloxy, alkoxylcarbonyl,arylalkoxycarbonyl, aminocarbonyl, alkylamino, dialkylamino,cycloalkylamino, cycloalkyl alkylamino, heterocyclyl alkylamino,heteroaryl, heteroarylamino, heteroarylalkylamino, dialkylaminoalkylamino, aryl, amino aryl, heteroaryl and heterocyclyl;heterocyclyl is unsubstituted or substituted by one or two of the sameor different groups selected from: halogen, hydroxy, alkoxy, oxo, alkyl,cycloalkyl, cycloalkyl alkyl, aryl, hydroxyalkyl, amino, aminoalkyl,alkylaminoalkyl, heterocyclyl alkyl, heteroaryl alkyl, aralkyl,alkylheteroaryl, cycloalkylheteroaryl, formyl, alkylcarbonyl,alkoxycarbonyl, aryl alkoxycarbonyl, cycloalkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, —SH, —S-alkyl, —S(O)₂-alkyl, —S(O)₂-aryl,alkylheteroaryl, cycloalkylheteroaryl, alkylamino andalkylheteroarylamino;aryl is unsubstituted or substituted by one or two of the same ordifferent groups selected from: halogen, nitro, alkyl, trifluoromethyl,alkoxy, amino, mono- or di-alkylamino, heteroaryl alkyl and aralkyl;heteroaryl is unsubstituted or substituted by one or two of the same ordifferent groups selected from: halogen, alkyl, cycloalkyl, nitro andamino;

W is S(O)_(m); and

m is the integer 0, 1 or 2;in all its stereoisomeric and tautomeric forms and mixtures thereof inall ratios, and its pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates, pharmaceutically acceptable polymorphs andprodrugs.

In one embodiment of a compound of formula 1 or 1a, the terms ‘alkyl’,‘cycloalkyl’, ‘alkoxy’, ‘alkenyl’, and ‘aryl’ are limited by theirrespective carbon content as follows: ‘Alkyl’ when used alone is ‘C₁-C₁₂alkyl’ and when used as part of a substituent group is ‘C₁-C₄ alkyl’,‘cycloalkyl’ is ‘C₃-C₆ cycloalkyl’, ‘alkoxy’ is ‘C₁-C₄ alkoxy’,‘alkenyl’ is ‘C₂-C₆ alkenyl’, and ‘aryl’ is ‘C₆-C₁₀ aryl’.

In further embodiments of any of the compounds of formula (1) or (1a),the groups R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ may, independently of eachother, have the following definitions. Hence, one or more of the groupsR₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ may have the preferred definitionsgiven below:

R₁ is hydrogen, C₁-C₄ alkyl or halogen;R₂ is hydrogen, halogen, amino, nitro, cyano, heterocyclyl, heterocyclylC₁-C₄alkylheterocyclyl, amino C₁-C₄ alkylheterocyclyl, aryl C₁-C₄alkylheterocyclyl, heteroarylbenzyl C₁-C₄ alkylheterocyclyl, heteroarylC₁-C₄ alkylheterocyclyl, di(C₁-C₄ alkyl)benzylheterocyclyl, C₃-C₆cycloalkylheterocyclyl, C₃-C₆ cycloalkylheteroaryl,heteroarylcarbonylheterocyclyl, heterocyclylsulfonyl,—S(O)₂—NH-heterocyclyl, C₁-C₄ alkylsulfonyl, C₁-C₄ alkoxy, C₃-C₆cycloalkylC₁-C₄alkyl, —NR₁₁R₁₂, NHR₁₆ or N=heterocyclyl;R₃ is hydrogen, NR₁₁R₁₂ or NHR₁₆;R₄ and R₅ are each independently selected from: hydrogen, halogen, C₁-C₄alkyl, nitro, amino, haloC₁-C₄alkylamino and heterocyclyl C₁-C₄alkylamino;R₆ and R₅ are each independently selected from: hydrogen, C₁-C₄ alkyland halogen;R₇ is hydroxy C₁-C₄ alkyl, chloro C₁-C₄ alkyl, cyano C₁-C₄ alkyl,formyl, —(CH₂)_(n)C(O)OR₁₀ or CONHR₁₆;R₁₀ is hydrogen, C₁-C₄ alkyl, amino C₁-C₄ alkyl, heterocyclyl C₁-C₄alkyl, aryl, heteroaryl or heterocyclyl;R₁₁ and R₁₂ are each independently selected from: hydrogen, C₁-C₄ alkyl,hydroxy C₁-C₄ alkyl, haloC₁-C₄ alkyl, aminoC₁-C₄ alkyl, arylC₁-C₄ alkyl,C₃-C₆cycloalkylC₁-C₄alkyl, C₆-C₁₀ aryl, heterocyclyl or heteroaryl; orR₁₁ and R₁₂, together with the N atom to which they are bonded, form a6- or 7-membered heterocyclyl, optionally having one or more additionalN or O heteroatoms;R₁₆ is formyl, C₁-C₄ alkyl, C₃-C₆cycloalkyl, heterocyclylC₁-C₄alkyl,heteroaryl C₁-C₆alkyl, heteroarylamino C₁-C₄ alkyl, di (C₁-C₄)alkylaminoC₁-C₄ alkyl, amino C₁-C₄ alkyl, heterocyclyl C₁-C₄alkylamino C₁-C₄alkyl, halo C₁-C₄ alkyl, di (C₁-C₄)alkyl amino C₁-C₄ alkyl aminoC₁-C₄alkyl, carboxy (C₁-C₄)alkyl, hydroxy C₁-C₄ alkyl, C₁-C₄alkylcarbonyl, trifluoromethylcarbonyl, di (C₁-C₄alkyl)aminoC₁-C₄alkylcarbonyl, C₃-C₆ cycloalkylaminoC₁-C₄alkylcarbonyl, haloC₁-C₄alkylcarbonyl, hydroxy C₁-C₄ alkylcarbonyl, C₁-C₄ alkylcarbonyl,C₁-C₄ alkyl aminoC₁-C₄alkylcarbonyl, C₆-C₁₀ aryl carbonyl,benzyloxycarbonyl, halo carbonyl C₁-C₄alkylcarbonyl, amino carbonylC₁-C₄alkylcarbonyl, C₁-C₄alkoxycarbonyl C₁-C₄alkylcarbonyl,C₁-C₄alkylcarbonyloxy C₁-C₄alkylcarbonyl or heterocyclyl C₁-C₄alkylcarbonyl;n is the integer 0, 1 or 2;where heterocyclyl is unsubstituted or substituted by one or two of thesame or different groups selected from: halogen, hydroxy, C₁-C₄ alkoxy,oxo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl C₁-C₄ alkyl, C₆-C₁₀aryl, hydroxy C₁-C₄ alkyl, amino, amino C₁-C₄ alkyl, C₁-C₄ alkylaminoC₁-C₄ alkyl, heterocyclyl C₁-C₄ alkyl, heteroaryl C₁-C₄alkyl, C₆-C₁₀aryl C₁-C₄ alkyl, C₁-C₄ alkylheteroaryl, C₃-C₁₀ cycloalkylheteroaryl,formyl, C₁-C₄alkylcarbonyl, C₁-C₄ alkoxycarbonyl, C₆-C₁₀ aryl C₁-C₄alkoxycarbonyl, C₆-C₁₀ arylcarbonyl, C₃-C₁₀ cycloalkylcarbonyl,heteroarylcarbonyl, —SH, —S—C₁-C₄ alkyl, —S(O)₂—C₁-C₄ alkyl,—S(O)₂—C₆-C₁₀ aryl, C₁-C₄ alkylheteroaryl, C₃-C₁₀ cycloalkylheteroaryl,C₁-C₄ alkylamino and C₁-C₄ alkylheteroarylamino;aryl is unsubstituted or substituted by one or two of the same ordifferent groups selected from: halogen, nitro, C₁-C₄alkyl,trifluoromethyl, C₁-C₄ alkoxy, amino, mono- or di-C₁-C₄ alkylamino,heteroaryl C₁-C₄ alkyl and C₆-C₁₀arC₁-C₄ alkyl; andheteroaryl is unsubstituted or substituted by one or two of the same ordifferent groups selected from: halogen, C₁-C₄ alkyl, C₃-C₄ cycloalkyl,nitro and amino.

In a further embodiment, a compound of formula (1) or (1a) is a compoundin which

R₂ is hydrogen, halogen, nitro, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,morpholinyl, [1,4]diazepanyl, 4-cyclopropyl-2-oxo-piperazinyl,piperazinyl, N-formyl piperazinyl, C₁-C₄ alkylcarbonyl piperazinyl,C₁-C₄alkyl piperazinyl, hydroxy C₁-C₄alkyl piperazinyl, C₁-C₄alkylsulfonyl piperazinyl, C₃-C₆ cycloalkyl piperazinyl, benzyl piperazinyl,C₁-C₄ alkoxycarbonyl piperazinyl, C₆-C₁₀ aryl C₁-C₄ alkoxycarbonylpiperazinyl, C₆-C₁₀ arylcarbonyl piperazinyl, aminoC₁-C₄alkylpiperazinyl, substituted phenyl C₁-C₄alkyl piperazinyl, imidazolylbenzylC₁-C₄alkyl piperazinyl, C₃-C₆cycloalkyl thiadiazolylpiperazinyl,pyrrolyl carbonylpiperazinyl, furanylC₁-C₄ alkylpiperazinyl,dimethylaminobenzyl piperazinyl, thiophenylC₁-C₄ alkylpiperazinyl,morpholinylC₁-C₄alkyl piperazinyl, C₁-C₄alkyl sulfonyl,piperazinylsulfonyl, isooxazolylaminosulfonyl, formyl amino, C₁-C₄alkylamino, dimethyl amino, C₁-C₄ alkylcarbonylamino, dimethylaminoC₁-C₄alkylcarbonylamino, C₃-C₆ cycloalkylaminoC₁-C₄alkylcarbonyl amino,hydroxy C₁-C₄alkylcarbonylamino, C₁-C₄alkylcarbonyloxyC₁-C₄alkylcarbonylamino, chloro C₁-C₄alkylcarbonylamino, morpholinylC₁-C₄ alkylcarbonylamino, trifluoromethylcarbonylamino,benzyloxycarbonylamino, piperazinylC₁-C₄alkylamino,morpholinylC₁-C₄alkylamino, phenylalkylamino, imidazolylamino C₁-C₄alkyl amino, imidazolyl C₁-C₄ alkyl amino, dimethylamino C₁-C₄alkylamino, isobutylamino, amino C₁-C₄ alkylamino, morpholinylC₁-C₄alkylamino C₁-C₄ alkylamino, morpholinyl C₁-C₄ alkylamino, C₃-C₆cycloalkylC₁-C₄alkylamino, chloro C₁-C₄alkylamino, dimethylaminoC₁-C₄alkylamino C₁-C₄ alkylamino, carboxy C₁-C₄ alkylamino, hydroxy C₁-C₄alkylamino, di(hydroxy C₁-C₄ alkyl)amino, chloro C₁-C₄alkylamino,di(chloroC₁-C₄alkyl)amino, benzyloxycarbonylC₁-C₄alkylamino, NR₁₁R₁₂ orpyrrolidin-2ylidene;R₁₁ and R₁₂ are each independently selected from: hydrogen, C₁-C₄ alkyl,morpholinyl C₁-C₄alkyl, C₆-C₁₀ aryl C₁-C₄ alkyl,C₃-C₆cycloalkylC₁-C₄alkyl, hydroxy C₁-C₄ alkyl, chloro C₁-C₄alkyl,C₆-C₁₀ aryl, heterocyclyl and heteroaryl; whereheterocyclyl is substituted with C₁-C₄alkyl; andaryl is substituted with one or two of the same or different groupsselected from: halogen, trifluoromethyl, C₁-C₄ alkyl, C₁-C₄ alkoxy andmono- or di-substituted amino;R₃ is hydrogen, amino, C₁-C₄alkylamino, amino C₁-C₄alkylamino,unsubstituted piperazinyl or piperazinyl substituted by C₁-C₄alkyl;R₄ is hydrogen or halogen; R₅ is hydrogen or C₁-C₄ alkyl; andR₇ is C(O)OC₁-C₄ alkyl, C(O)OH, CH₂C(O)OC₁-C₄ alkyl, CH₂C(O)OH, formyl,hydroxy C₁-C₄ alkyl, chloro C₁-C₄ alkyl, cyano C₁-C₄ alkyl or —C(O)NHC₃-C₆ cycloalkyl.

In a further embodiment, a compound of formula (1) or (1a) is a compoundin which

R₂ is amino, formylamino, C₁-C₄alkylamino, C₁-C₄alkylcarbonylamino,chloro C₁-C₄alkylcarbonylamino, hydroxy C₁-C₄alkylcarbonylamino,C₁-C₄alkyl carbonyloxy C₁-C₄alkylcarbonylamino, carboxyC₁-C₄alkylamino,di(chloroC₁-C₄alkyl)amino, di(hydroxyC₁-C₄alkyl)amino, acetamide,propionamide, morpholinyl, [1,4]diazepanyl, unsubstituted piperazinyl orpiperazinyl substituted by at least one group selected from: C₁-C₄alkyl,C₃-C₆cycloalkyl, formyl, C₁-C₄alkylcarbonyl, hydroxy C₁-C₄alkyl,C₁-C₄alkylsulfonyl, benzyl, oxo, C₁-C₄ alkoxycarbonyl,benzyloxycarbonyl, unsubstituted C₆-C₁₀ arylcarbonyl or C₆-C₁₀arylcarbonyl substituted by at least one group selected from:C₁-C₄alkyl, C₁-C₄alkoxy, halogen and trifluoromethyl;R₃ is hydrogen;R₄ is halogen; R₅ is C₁-C₄ alkyl; andR₇ is C(O)OC₁-C₄ alkyl, C(O)OH, CH₂C(O)OC₁-C₄ alkyl or CH₂C(O)OH.

In yet another embodiment, a compound of formula (1) or (1a) is acompound in which

R₁ and R₂ are hydrogen;R₃ is amino, amino C₁-C₄alkylamino, unsubstituted piperazinyl orpiperazinyl substituted by C₁-C₄alkyl;R₄ is chloro, bromo or fluoro;R₅ is methyl or ethyl;R₆ and R₈ are hydrogen; andR₇ is C(O)OC₁-C₄ alkyl, C(O)OH.

In yet another embodiment, a compound of formula (1) or (1a) is acompound in which

R₁ is hydrogen;R₂ is unsubstituted piperazinyl or piperazinyl substituted byC₁-C₄alkyl, C₃-C₆cycloalkyl, formyl, C₁-C₄ alkylcarbonyl, hydroxyC₁-C₄alkyl, C₁-C₄alkylsulfonyl, benzyl, oxo, C₁-C₄ alkoxycarbonyl,benzyloxycarbonyl, unsubstituted C₆-C₁₀ arylcarbonyl or C₆-C₁₀arylcarbonyl substituted by C₁-C₄alkyl;R₃ is hydrogen;R₄ is chloro, bromo or fluoro;R₅ is methyl or ethyl; andR₆ and R₈ are hydrogen.

In yet another embodiment, a compound of formula (1) or (1a) is acompound in which W is SO₂.

In another embodiment, the present invention provides novel tricycliccompounds represented by the following formula 1a′:

whereinR₂ is hydrogen, halogen, hydroxy, alkyl, cycloalkyl, alkoxy, cyano,nitro, trifluoromethyl, aryl, heterocyclyl, heteroaryl, —(CH₂)_(n)C(O)R₉or NR₁₁R₁₂;R₄ and R₅ are each independently selected from: hydrogen, halogen,hydroxy, trifluoromethyl, alkyl, cycloalkyl, alkenyl, alkoxy, aryl,heteroaryl and heterocyclyl;R₇ is —(CH₂)_(n)C(O)R₉;R₉ is hydrogen, halogen, alkyl, cycloalkyl, aralkyl, trifluoromethyl,OR₁₀, aryl or heterocyclyl;R₁₀ is hydrogen, alkyl, cycloalkyl, trifluoromethyl, aryl orheterocyclyl;R₁₁ and R₁₂ are each independently selected from: hydrogen, alkyl,cycloalkyl, alkylamino, aryl, heteroaryl, heterocyclyl, —(CH₂)_(n)C(O)R₉and cycloalkylaminoalkylcarbonyl; or R₁₁ and R₁₂, together with the Natom to which they are bonded, form a 5-, 6-, 7- or 8-memberedheterocyclyl, optionally having one or more additional heteroatomsselected from: O, N and S;

U is C(O), CR₁₃R₁₄ or NR₁₅;

R₁₃ is H, alkyl, cycloalkyl or alkenyl;

R₁₄ is H, OH, OR₁₃ or OCOR₁₃;

R₁₅ is H or alkyl; andn is the integer 0, 1 or 2;where alkyl or cycloalkyl is unsubstituted or substituted by one or twoof the same or different groups selected from: halogen, hydroxy,alkylcarboxy, amino, cycloalkyl, alkoxy, aryloxy, alkoxylcarbonyl,arylalkoxycarbonyl, aminocarbonyl, alkylamino, dialkylamino,cycloalkylamino, cycloalkylalkylamino, heterocyclylalkylamino,heteroaryl, heteroarylamino, heteroarylalkylamino,dialkylaminoalkylamino, aryl, aminoaryl, heteroaryl and heterocyclyl;heterocyclyl is unsubstituted or substituted by one or two of the sameor different groups selected from: halogen, hydroxy, alkoxy, oxo, alkyl,cycloalkyl, cycloalkyl alkyl, aryl, hydroxyalkyl, amino, aminoalkyl,alkylaminoalkyl, heterocyclylalkyl, heteroarylalkyl, aralkyl,alkylheteroaryl, cycloalkylheteroaryl, formyl, alkylcarbonyl,alkoxycarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,—SH, —S-alkyl, —S(O)₂-alkyl, —S(O)₂-aryl, alkylheteroaryl,cycloalkylheteroaryl, alkylamino and alkylheteroarylamino;aryl is unsubstituted or substituted by one or two of the same ordifferent groups selected from: halogen, nitro, alkyl, trifluoromethyl,alkoxy, amino, mono- or di-alkylamino, heteroarylalkyl and aralkyl;heteroaryl is unsubstituted or substituted by one or two of the same ordifferent groups selected from: halogen, alkyl, cycloalkyl, nitro andamino;in all its stereoisomeric and tautomeric forms and mixtures thereof inall ratios, and its pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates, pharmaceutically acceptable polymorphs andprodrugs.

In one embodiment of a compound of formula 1′ or 1a′, the terms ‘alkyl’,‘cycloalkyl’, ‘alkoxy’, ‘alkenyl’, and ‘aryl’ are limited by theirrespective carbon content as follows: ‘Alkyl’ when used alone is ‘C₁-C₁₂alkyl’ and when used as part of a substituent group is ‘C₁-C₄ alkyl’,‘cycloalkyl’ is ‘C₃-C₆ cycloalkyl’, ‘alkoxy’ is ‘C₁-C₄ alkoxy’,‘alkenyl’ is ‘C₂-C₆ alkenyl’, and ‘aryl’ is ‘C₆-C₁₀ aryl’.

In embodiments of any of the compounds of formula (1′) or (1a′), thegroups R₂, R₄, R₅, R₇ and U may, independently of each other, have thefollowing definitions. Hence one or more of the groups R₂, R₄, R₅, R₇and U may have the preferred definitions given below:

R₂ is hydrogen, nitro, amino, C₁-C₄alkylamino or formylamino;R₄ is hydrogen or chloro;R₅ is hydrogen or methyl;R₇ is C(O)OC₁-C₄alkyl or C(O)OH;

U is NH, CO, CHOH or CH₂.

In an even further preferred embodiment, the present invention providestricyclic compounds selected from the following:

-   2-Amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   2-Amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid;-   2-Amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid sodium salt;-   4-Chloro-2-(2-chloro-acetylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   4-Chloro-2-(2-hydroxy-acetylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   2-(2-Acetoxy-acetylamino)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   4-Chloro-6-methyl-10,10-dioxo-2-propionylamino-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   4-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid;-   4-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid sodium salt;-   4-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   4-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid ethyl ester;-   4-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid isopropyl ester;-   2-[Bis-(2-chloro-ethyl)amino]-4-chloro-6-methyl10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylic    acid methyl ester;-   2-[Bis-(2-hydroxy-ethyl)-amino]-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda    *6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester;-   4-Chloro-6-methyl-2-piperazin-1-yl-11H-5-oxa-10-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester hydrochloride;-   4-Chloro-6-methyl-10-oxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*4*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester hydrochloride;-   4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylic    acid methyl ester hydrochloride;-   4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester mesylate;-   4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid;-   4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid mesylate;-   4-Chloro-2-(4-formyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   2-(4-Acetyl-piperazin-1-yl)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   4-Chloro-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   2-(4-Benzyl-piperazin-1-yl)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   4-Chloro-6-methyl-2-[4-(2-methyl-benzoyl)-piperazin-1-yl]-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   4-Chloro-2-(4-methanesulfonyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   4-(4-Chloro-8-methoxycarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-piperazine-1-carboxylic    acid benzyl ester;-   4-Chloro-2-(4-cyclopropyl-2-oxo-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester hydrochloride;-   4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid isopropyl ester;-   4-Chloro-2-[1,4]diazepan-1-yl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester hydrochloride;-   4-Chloro-6-methyl-2-morpholin-4-yl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   3-(2-Amino-ethylamino)-4-Chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester hydrochloride;-   4-Chloro-6-methyl-10,10-dioxo-3-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester hydrochloride;-   (4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-yl)-acetic    acid methyl ester hydrochloride;-   4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbaldehyde;-   [4-Chloro-2-(4-ethyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-yl]-methanol;-   4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid cyclopropylamide hydrochloride;-   2-Amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a,d]-cycloheptene-8-carboxylic    acid methylester;-   4-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5H-10-lambda*6*-thia-5-aza-dibenzo[a,d]-cycloheptene-8-carboxylic    acid methyl ester;-   5-10,10-Trioxo-10,11-dihydro-5H-10-lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;-   5-Hydroxy-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester; and-   10,10-Dioxo-10,11-dihydro-5H-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic    acid methyl ester;

All the compounds of the present invention also include allstereoisomeric forms and mixtures thereof in all ratios and theirpharmaceutically acceptable salts, solvates and polymorphs. Furthermore,all the compounds of the present invention are a subject of the presentinvention in the form of their prodrugs and other derivatives, forexample in the form of their esters and amides.

According to a further feature of the present invention there areprovided processes for the synthesis of compounds of the presentinvention of general formula (1) or (1′), more particularly thecompounds of the general formula (1a) or (1a′).

One such process for the preparation of a compound of formula (1a) or(1a′)

wherein U is O and W is SO₂, SO or S (formula (1a) or U is NH and W isSO₂ (formula (1a′)); R₂, R₃, R₄, R₅ and R₇ are as defined above,comprises subjecting a compound of formula E:

wherein U is O and W is SO₂, SO or S (formula (1a) or U is NH and W isSO₂ (formula (1a′), R₄, R₅ and R₇ are as defined above, to nitrationusing any standard procedure known in the art to obtain a nitroderivative of general formula E1 (major component) or E1′ (minorcomponent):

wherein U is O or NH, and W, R₄, R₅ and R₇ are as defined above.

The resulting nitro derivative of the general formula E1 or E1′ may besubjected to reduction by using any conventional reduction method knownto one skilled in the art, to obtain an amino derivative of the generalformula E2 or E2′, respectively:

wherein U is O or NH, and W, R₄, R₅ and R₇ are as defined above.

In the process described above, W is preferably SO₂.

The amino derivative of the general formula E2 or E2′ may further befunctionalised/derivatised at the primary amino group, and/or at anamino group located at any other position of the compound, by subjectingit to a series of reactions to obtain various derivatives, which arealso incorporated in the general formula (1) or (1′). The resultingcompound may be converted into a pharmaceutically acceptable salt orprodrug.

The amino derivative of the general formula E2 or E2′ or any othercompound of the formula 1, 1′, 1a or 1a′, in which R₇ represents alkylcarboxylate, may be subjected to alkaline hydrolysis to obtain an acidand then may be reacted with an amine to form a substituted orunsubstituted amide. The resulting compound may optionally be convertedinto a pharmaceutically acceptable salt.

The amino derivative of the general formula E2 or E2′ or any othercompound of the formula 1, 1′, 1a or 1a′, in which R₇ represents alkylcarboxylate, may be subjected to hydrolysis followed by standardreduction reactions to form a —CH₂OH derivative, which further may beoxidized to —CHO. The resulting compound may optionally be convertedinto a pharmaceutically acceptable salt or prodrug.

The amino derivative of the general formula E2 or E2′ or any othercompound of the formula 1, 1′, 1a or 1a′, in which R₇ represents —CH₂OHmay be subjected to standard reactions to convert R₇ into —CH₂Cl, whichfurther can be converted to —CH₂CN, which in turn can be converted to—CH₂COOH by hydrolysis and which may further be esterified to form anester such as —CH₂COOC₁-C₄alkyl. The resulting compound may optionallybe converted into a pharmaceutically acceptable salt or prodrug.

The compound of formula E (above) is prepared by either

a) subjecting a compound of formula D

wherein W is SO₂, SO or S, and R₄, R₅ and R₇ are as defined hereinabove, L is NO₂ or NH₂, and X is halogen, to reduction where L is NO₂ toconvert the NO₂ into NH₂ and then cyclisation to obtain the cycliccompound of the general formula E (wherein R₄, R₅ and R₇ are as definedherein above; and U is NH), orb) subjecting a compound of the general formula D (wherein R₄, R₅ and R₇are as defined herein above; L is protected hydroxy group; and X ishalogen) to deprotection to obtain the corresponding hydroxy compound,subjecting the hydroxyl compound to cyclisation to obtain a compound ofthe general formula E (wherein R₄, R₅ and R₇ are as defined hereinabove; and U is O).

In a preferred embodiment, W in the compound of formula D above is SO₂.

The compound of the formula D (above) may be obtained by alkylating anappropriately substituted o-halo mercaptobenzoic acid of the formula A:

wherein X is a halogen, R₇ is an alkyl carboxylate, R₅ is as definedabove, with an appropriately substituted1-halomethyl-2-(protected)hydroxybenzene or 1-halomethyl-2-nitrobenzeneof formula B:

wherein X is a halogen, L is either protected hydroxy or nitro, R₄ is asdefined above, to obtain a sulfanyl compound of the formula C:

wherein X is halogen and L is a protected hydroxy group, such ast-butyl-dimethylsilyloxy or nitro, R₇ is alkyl carboxylate, R₄ and R₅are as defined above; and optionally oxidizing the compound of formula Cto its sulfoxide or sulfonyl derivative.

The compounds of the present invention can be prepared in a number ofways using methods well known to the skilled person. Examples of methodsto prepare the present compounds are described below and illustrated inScheme I but not limited thereto. It will be appreciated by personsskilled in the art that within certain of the processes describedherein, the order of the synthetic steps employed may be varied and willdepend inter alia on factors such as the nature of functional groupspresent in a particular substrate and the protecting group strategy (ifany) to be adopted. Clearly, such factors will also influence the choiceof reagent to be used in the synthetic steps.

The reagents, reactants and intermediates used in the followingprocesses are either commercially available or can be prepared accordingto standard literature procedures known in the art. The startingcompounds and the intermediates used for the synthesis of compounds ofthe present invention, are referred to with general symbols namely A,A-i, A-ii, A-iii, A-iv, B, B-i, B-ii, C, D, E, E1, E1′, G-i. P, Q, Q1,Q2, E2 and E2′ of which the compounds designated as A, B, C, D, E, E1,E1′, P, Q, Q1, Q2, Q3, E2 and E2′ are the key intermediates. The keyintermediates B, C, D, E, E1, E1′, E2 and E2′ may represent more thanone type of compound depending on the definition of the U group. Forinstance:

1. In the intermediates of general formula B, C and D, the substituent Lmay represent a group selected from amino, nitro and a protected hydroxygroup, wherein the protective group may be selected fromt-butyl-dimethylsilyl (TBDMS), acetyl, and the like;2. In the intermediate of general formula E, E1, E1′, E2 and E2′ the Ugroup may be selected from O or NH.

Throughout the process description, the corresponding substituent groupsin the various formulae representing starting compounds andintermediates have the same meanings as that for the compounds offormula (1a) or (1a′) unless stated otherwise.

A general route for the synthesis of compounds of the present inventioninvolves: alkylation of an appropriately substituted o-bromomercaptobenzoic acid (A) with an appropriately substituted(2-halomethylphenoxy) tert-butyldimethylsilane (B), followed byoxidation of the resulting sulfanyl derivative (C) to its sulfonylderivative (D). The sulfonyl derivative (D), thus obtained may then besubjected to deprotection of the silyl ether group followed by in situcyclisation and a series of reaction steps (understood by those skilledin the art) for suitable modification of the functional groups, toobtain a desired compound of the invention, more particularly a compoundof the general formula (1a) or (1a′). Alternatively, the sulfanylderivative (C) may be subjected to a series of reactions involvingdesilylation and cyclisation, followed by nitration which may result inpartial oxidation of the ring sulfur atom into its sulfoxide (Q1) whichmay be converted to a desired compound of the invention, moreparticularly to a compound of the general formula (1a) or (1a′) bystandard procedures known to those skilled in the art.

Alternatively, alkylation of an appropriately substituted o-bromomercaptobenzoic acid (A) may be carried out with an appropriatelysubstituted 1-halomethyl-2-nitrobenzene (B), to obtain a sulfanylderivative (C) which may then be oxidized to its sulfonyl derivative(D). The resulting sulfonyl derivative (D), wherein L is NO₂ may besubjected to reduction with an appropriate reducing agent for theconversion of nitro to amino group, followed by cyclisation and a seriesof reaction steps (understood by those skilled in the art) for suitablemodification of the functional groups, to obtain a desired compound ofthe invention, more particularly a compound of the general formula (1a)or (1a′).

Preferred processes for the preparation of compounds of the presentinvention are set forth in the following Scheme I:

Process 1: Preparation of key intermediates of general formula E2 orE2′:

Step (i): Preparation of the Compounds of General Formula C:

A thiol compound of the general formula A (wherein R₅ is as definedherein above; R₇ represents alkyl carboxylate; X represents halogen,preferably Br) may be subjected to a nucleophilic substitution, moreparticularly to an S alkylation, with a compound of the general formulaB (wherein R₄ is as defined herein above; X represents halogen,preferably Br; and L represents a protected hydroxy group such ast-butyl-dimethylsilyloxy), in the presence of a base in an aproticsolvent, over a time period of 0.5 h to 10 h, at a temperature range of0° C. to ambient, in the presence or absence of an inert atmosphereusing gases such as N₂, Ar, He, and processed in a manner known to oneskilled in the art to obtain the sulfanyl derivative, a compound of thegeneral formula C (wherein R₄ and R₅ are as defined herein above; R₇represents alkyl carboxylate; X represents halogen, preferably Br; and Lrepresents a protected hydroxy group such as thet-butyl-dimethylsilyloxy group). When the thiol compound of the generalformula A is alkylated with the compound of general formula B (wherein Lrepresents NO₂), the key intermediate of formula C (wherein R₄ and R₅are as defined herein above; R₇ represents alkyl carboxylate; Xrepresents halogen, preferably Br; and L represents NO₂) is obtained.

The base used in the above substitution reaction may be an organic or aninorganic base. The organic base may be selected from triethylamine,pyridine, lutidine, collidine or a mixture thereof. The inorganic basemay be selected from sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydride, potassium hydride,sodamide, n-butyllithium. The amount of base used may range from 1 to 5equivalents, preferably 1 to 3 equivalents of the starting compound ofgeneral formula A.

The aprotic solvent, in which the above substitution reaction is carriedout, may be selected from a hydrocarbon such as hexane, benzene,toluene, xylene; or a halogenated hydrocarbon such as dichloroethane,chloroform; or an ether such as tetrahydrofuran (THF), dioxane, diethylether, t-butyl methyl ether; or any other solvent such as DMF or DMSOsuitable for carrying out the substitution reaction.

Step (ii): Conversion of the Compounds of Formula C to the Compounds ofFormula D:

The compounds of the general formula C, as obtained in the above step(i) (wherein R₄ and R₅ are as defined herein above, R₇ represents alkylcarboxylate; L represents t-butyl-dimethylsilyloxy or NO₂; and Xrepresents halogen, preferably Br), may be oxidized using an oxidizingagent selected from hydrogen peroxide; m-chloroperbenzoic acid (m-CPBA),potassium perchlorate or OXONE™, preferably m-CPBA, in the presence ofan organic solvent selected from a halogenated hydrocarbon such asdichloromethane and a protic solvent such as methanol, ethanol and thelike, at a temperature range of 0° C. to reflux, over a time period of 1h to 8 h, and further processed in a manner known to one skilled in theart to obtain the corresponding sulfonyl derivative, a compound of thegeneral formula D (wherein R₄ and R₅ are as defined herein above; R₇represents alkyl carboxylate; L represents t-butyl-dimethylsilyloxy orNO₂; and X represents halogen, preferably Br).

The compound of formula D (wherein L represents NO₂) may be subjected toreduction with an appropriate reducing agent to obtain its correspondingamine derivative, a compound of formula D (wherein R₄ and R₅ are asdefined herein above; R₇ represents alkyl carboxylate; L represents NH₂;and X represents halogen, preferably Br).

The reduction reaction may be carried out using various reductionmethods known to one skilled in the art, for example, by catalytichydrogenation in presence of a catalyst such as Raney Nickel,palladium-carbon, platinum-carbon, rhodium-carbon. Other reductionmethods such as those involving use of sodium borohydride, sodiumcyanoborohydride, tin-hydrochloric acid or iron-hydrochloric acid, mayalso be used for carrying out the reduction reaction. However, thereduction method involving catalytic hydrogenation using Raney Nickel asthe catalyst, is the preferred method.

The organic solvent used for carrying out the reduction reaction may beselected from N,N-dimethylformamide (DMF), tetrahydrofuran (THF), ethylacetate, ethanol, methanol, toluene, benzene, diethyl ether, dioxane;and DMF being the preferred solvent.

Step (iii): Conversion of the Compounds of Formula D to the Compounds ofFormula E.

The compound of the general formula D as obtained in the above step (ii)(wherein R₄ and R₅ are as defined herein above; R₇ represents alkylcarboxylate; L represents NH₂; and X represents halogen, preferably Br)may undergo cyclisation in the presence of an inorganic base such assodium hydride. The cyclisation reaction may be carried out in anaprotic solvent such as DMF, in the presence or absence of an inertatmosphere, at a temperature range of 0° C. to 100° C., over a timeperiod of 2 h to 24 h to obtain the cyclic intermediate, a compound ofthe general formula E (wherein R₄ and R₅ are as defined herein above; R₇represents alkyl carboxylate; and U represents NH).

Alternatively, the compound of the general formula D (wherein R₄ and R₅are as defined herein above; R₇ represents alkyl carboxylate; Lrepresents t-butyl-dimethylsilyloxy; and X represents halogen,preferably Br) may be subjected to deprotection of the silyl ether groupusing a suitable deprotecting reagent such as tetraalkylammoniumfluoride to obtain the corresponding hydroxy compound which may alsoundergo in situ cyclisation to obtain the cyclic intermediate, acompound of the general formula E (wherein R₄ and R₅ are as definedherein above; R₇ represents alkyl carboxylate; and U represents O).

Step (iv): Conversion of the Compounds of Formula E to the Compounds ofFormula E1 or E1′.

The compound of general formula E as obtained in the above step (ii)(wherein R₄ and R₅ are as defined herein above; R₇ represents alkylcarboxylate) may be subjected to nitration using nitric acid-sulfuricacid as per any standard nitration procedure known in the art. Forinstance, the nitration reaction may be carried out at a temperaturerange of 0° C. to 40° C., over a time period of 1 h to 20 h to obtainthe corresponding nitro derivative, a compound of the general formula E1(wherein R₄ and R₅ are as defined herein above; R₂ represents NO₂; andR₇ represents alkyl carboxylate) or E1′ (wherein R₄ and R₅ are asdefined herein above; R₃ represents NO₂; and R₇ represents alkylcarboxylate).

Step (v): Conversion of the Compounds of Formula E1 or E1′ to theCompounds of Formula E2 or E2′.

The nitro group in the compound of formula E1 or E1′ as obtained in theabove step (iv) (wherein R₄ and R₅ are as defined herein above; R₂ or R₃represents NO₂ and R₇ represents alkyl carboxylate) may be subjected toreduction by using a suitable reducing agent in an organic solvent atambient temperature and worked up in a manner known to one skilled inthe art, to obtain the corresponding amino derivative, a compound of thegeneral formula E2 (wherein R₄ and R₅ are as defined herein above; R₂represents NH₂; and R₇ represents alkyl carboxylate) or E2′ (wherein R₄and R₅ are as defined herein above; R₃ represents NH₂; and R₇ representsalkyl carboxylate).

The reduction reaction may be carried out using various reductionmethods known to one skilled in the art, for example, by catalytichydrogenation in presence of a catalyst such as Raney Nickel,palladium-carbon, platinum-carbon, Rhodium-carbon. Other reductionmethods such as those involving use of sodium borohydride, sodiumcyanoborohydride, tin-hydrochloric acid (Sn—HCl) or iron-hydrochloricacid (Fe—HCl), may also be used for carrying out the reduction reaction.However, the reduction method involving catalytic hydrogenation usingRaney Nickel as the catalyst, is the preferred method. The organicsolvent used for carrying out the reduction reaction may be selectedfrom dimethylformamide (DMF), tetrahydrofuran (THF), ethyl acetate,ethanol, methanol, toluene, benzene, diethyl ether, dioxane; and DMFbeing the preferred solvent.

Process 2: Preparation of the Key Intermediates of General Formulae P,Q, Q1, Q2, Q3 and E2: Step (i): Preparation of the Key Intermediate ofGeneral Formula P:

A compound of the general formula C as obtained in Process 1-step (i)(wherein R₄ and R₅ are as defined herein above; R₇ represents alkylcarboxylate; L represents t-butyl-dimethylsilyloxy; and X representshalogen, preferably Br) may be subjected to deprotection of the silylether group by treating the said compound with a suitable deprotectingreagent in an appropriate organic solvent in the presence or absence ofan inert atmosphere using a gas such as nitrogen at a temperature rangeof 0° C. to reflux over a time period of 0.5 h to 3 h (as reported inTetrahedron, 1985, 41, 3257) to obtain the hydroxy intermediate, acompound of the general formula P (wherein R₄ and R₅ are as definedherein above; R₇ represents alkyl carboxylate; and X represents halogen,preferably Br).

The deprotecting agent used in the above step may be selected from achemoselective reagent such as tetraalkylammonium halide, preferablytetrabutylammonium fluoride, and any other suitable deprotecting agentsuch as hydrogen fluoride (HF), HF-pyridine, acetic acid,trifluoroacetic acid (TFA), hydrochloric acid.

The organic solvent in which the deprotection (desilylation) reaction iscarried out may be selected from tetrahydrofuran (THF), methanol,methylene dichloride, chloroform, benzene, toluene and any othersuitable solvent.

Step (ii): Conversion of the Compound of Formula P to the Compound ofFormula Q:

The compound of the general formula P as obtained in the above step (i)(wherein R₄ and R₅ are as defined herein above; R₇ represents alkylcarboxylate; and X represents halogen, preferably Br) may undergocyclisation in the presence of a base such as potassium carbonate. Thecyclisation may be carried out in an aprotic solvent such as DMF, in thepresence or absence of an inert atmosphere, at a temperature range of 0°C. to 100° C., over a time period of 2 h to 24 h to obtain the cyclicintermediate, a compound of the general formula Q (wherein R₄ and R₅ areas defined herein above; R₇ represents alkyl carboxylate).

Step (iii): Conversion of the Compound of Formula Q to the Compound ofFormula Q1:

The compound of general formula Q as obtained in the above step (ii)(wherein R₄ and R₅ are as defined herein above; R₇ represents alkylcarboxylate) may be subjected to nitration using nitric acid-sulfuricacid as per any standard nitration procedure known in the art. Forinstance, the nitration reaction may be carried out at a temperaturerange of 0° C. to 40° C., over a time period of 1 h to 20 h to obtainthe corresponding nitro derivative, a compound of the general formula Q1(wherein R₄ and R₅ are as defined herein above; R₂ represents NO₂; andR₇ represents alkyl carboxylate). This reaction may also result in thepartial oxidation of the ring sulfur atom into its sulfoxide.

Step (iv): Conversion of the Compound of Formula Q1 to the Compound ofFormula Q2:

The nitro group in the compound of formula Q1 as obtained in the abovestep (iii) (wherein R₄ and R₅ are as defined herein above; R₂ representsNO₂; and R₇ represents alkyl carboxylate) may be subjected to reductionby using a suitable reducing agent in an organic solvent at ambienttemperature and worked up in a manner known to one skilled in the art,to obtain the corresponding amino derivative, a compound of the generalformula Q2 (wherein R₄ and R₅ are as defined herein above; R₂ representsNH₂; and R₇ represents alkyl carboxylate).

The reduction reaction may be carried out using various reductionmethods known to one skilled in the art, for example, by catalytichydrogenation in presence of a catalyst such as Raney nickel,palladium-carbon, platinum-carbon, Rhodium-carbon. Other reductionmethods such as those involving use of sodium borohydride, sodiumcyanoborohydride, tin-hydrochloric acid (Sn—HCl) or iron-hydrochloricacid (Fe—HCl), may also be used for carrying out the reduction reaction.However, the reduction method involving catalytic hydrogenation usingRaney nickel as the catalyst, is the preferred method.

The organic solvent used for carrying out the said reduction reactionmay be selected from dimethylformamide (DMF), tetrahydrofuran (THF),ethyl acetate, ethanol, methanol, toluene, benzene, diethyl ether,dioxane; and DMF being the preferred solvent.

Step (vi): Conversion of the Compounds of Formula Q2 to the Compounds ofFormula Q3:

The compounds of the general formula Q2, as obtained in the above step(i) (wherein R₄ and R₅ are as defined herein above; R₂ represents NH₂;and R₇ represents alkyl carboxylate; W is SO), may be reduced usingstandard procedures to obtain the compounds of the general formula Q3(wherein R₄ and R₅ are as defined herein above; R₂ represents NH₂; andR₇ represents alkyl carboxylate; W is S).

Step (vi): Conversion of the Compounds of Formula Q2 to the Compounds ofFormula E2:

The compounds of the general formula Q2, as obtained in the above step(i) (wherein R₄ and R₅ are as defined herein above; R₂ represents NH₂;and R₇ represents alkyl carboxylate), may be oxidized using an oxidizingagent selected from hydrogen peroxide; m-chloroperbenzoic acid (m-CPBA),potassium perchlorate and OXONE™, preferably m-CPBA, in the presence ofan organic solvent selected from a halogenated hydrocarbon such asdichloromethane and a protic solvent such as methanol, ethanol and thelike, at a temperature range of 0° C. to reflux, over a time period of 1h to 8 h, and further processed in a manner known to one skilled in theart to obtain the corresponding sulfonyl derivative, a compound of thegeneral formula (1a) or (1a′) (wherein R₄ and R₅ are as defined hereinabove; R₂ represents NH₂; and R₇ represents alkyl carboxylate).

Process 3: Conversion of the Key Intermediates of Formulae E, E1, E1′,Q2, Q3, E2 and E2′ to the Respective Acids.

The key intermediates, the compounds of the general formulae E, E1, E1′,Q2, Q3, E2 and E2′ as obtained according to the above describedprocesses (wherein R₂, R₃, R₄, R₅ and U are as defined herein above; R₇represents a carboxylate ester group such as alkylcarboxylate orcycloalkylcarboxylate or substituted cycloalkyl carboxylate group,preferably the methyl carboxylate) may be subjected to hydrolysis usingacidic conditions or alkaline conditions, more preferably using analkali such as sodium hydroxide, in a solvent or a solvent mixture suchas THF-water at a temperature range of 0° C. to 60° C., over a timeperiod of 0.5 h to 10 h, and worked up in a manner known to one skilledin the art to obtain the corresponding carboxylic acids represented bythe general formulae E, E1, E1′, Q2, Q3, E2 and E2′ (wherein R₂, R₃, R₄,R₅ and U are as defined herein above; R₇ represents —COOH).

Process 4: Derivatisation of the Key Intermediate of Formula Q2, Q3, E2and E2′.

It will be appreciated by one skilled in the art that compounds whichfall within the general formula Q2, Q3, E2 and E2′, may in someinstances, be functionalised to obtain further derivatives.

Any one of the compounds represented by the general formula Q2, Q3, E2and E2′, in Scheme-I (wherein R₄ and R₅ are as defined herein above; R₂or R₃ represents NH₂; R₇ represents carboxylic acid or alkyl carboxylategroup; U is O or NH) may further be functionalised/derivatised at theprimary amino group (R₂ or R₃) by subjecting it to a series of reactionsknown in the literature to obtain various derivatives, represented bythe general formula (1a) or (1a′).

The compounds represented by the general formula Q2, Q3, E2 and E2′, inScheme-I (wherein R₄ and R₅ are as defined herein above; R₂ or R₃represents NH₂; R₇ represents carboxylic acid; U is O or NH) and theamino derivatives (mentioned above) may further befunctionalised/derivatised by reacting with suitable amines to obtainsubstituted or unsubstituted amide.

The compounds represented by the general formula Q2, Q3, E2 and E2′, andthe derivatives obtained in above step, in which R₇ represents alkylcarboxylate, may be subjected to hydrolysis followed by standardreduction reactions to form the —CH₂OH derivatives which may be oxidizedto obtain the formyl derivative. The derivatives obtained in above stepin which R₇ represents —CH₂OH may be subjected to standard reactions toform —CH₂Cl, which further can be converted to —CH₂CN using NaCN, whichcan be converted to —CH₂COOH by hydrolysis and to —CH₂COOC₁-C₄alkyl byesterification.

These derivatives may subsequently be converted into their organic orinorganic salts, like the methane sulfonic acid salts, by treatment withmethane sulfonic acid in a dry solvent like ethyl acetate, dioxane,diethyl ether, methanol, ethanol or any other suitable solvent andprocessed in a manner known to one skilled in the art.

Process 5: Preparation of the Thiol Compound of General Formula A: Step(i): Preparation of Compounds of the General Formulae A-i and A-ii:

An appropriately substituted aryl halide, preferably an appropriatelysubstituted 4-halo-benzoic acid of general formula A-i (wherein R₅ is asdefined herein above; R₇ represents COOH; and X represents halogen,preferably Br) may be treated with chlorosulfonic acid at a temperaturerange of 40° C. to 140° C., for a time period of 4 h to 24 h byfollowing a standard procedure to obtain the correspondingchlorosulfonyl derivative, a compound of general formula A-ii (whereinR₅ is as defined herein above; R₇ represents COOH; and X representshalogen, preferably Br).

The compound of formula A-i may be either commercially available or beobtained by subjecting an appropriately substituted 4-nitro-benzoic acidto a sequence of reactions namely reduction, diazotisation and aSandmeyer reaction. For example, the nitro group in the 4-nitrobenzoicacid may be reduced to the corresponding amine by catalytichydrogenation or transfer hydrogenation, with ammonium formate inpresence of a catalyst such as Pd, Pt, Pd—C, Raney-Ni, in an organicsolvent such as ethyl acetate, methanol, ethanol, isopropanol, DMF, or amixture thereof. This reduction may also be carried out by anyconventional method known in the art, such as that involving use of Znand HCl or CoCl₂ (Ind. J. Chem., 1994, 33B, 758) or NaBH₄. The resultingamino compound may then be subjected to diazotisation followed by aSandmeyer reaction to obtain the desired compound of general formula A-i(wherein R₅ is as defined herein above; R₇ represents COOH; and Xrepresents halogen, preferably Br).

Step (ii): Conversion of the Compounds of Formula A-ii to the Compoundsof Formula A-iii:

A compound of the general formula A-ii as obtained in the above step (i)(wherein R₅ is as defined herein above; R₇ represents COOH; and Xrepresents halogen, preferably Br) may be subjected to reduction underacidic condition, preferably the reduction reaction may be carried outusing glacial acetic acid-stannous chloride in HCl—H₂O (4:1v/v) withstirring, at a temperature of 80° C. for a time period of 1 h to obtaina thiol compound of general formula A-iii (R₅ is as defined hereinabove; R₇ represents COOH; and X represents halogen, preferably Br). Inthe process of this reaction a disulfide is also obtained as a majorby-product, which may be converted to its thiol compound of formulaA-iii by subjecting it to reductive cleavage using triphenylphosphine inaqueous methanol as reported in (Synthesis, 59, 1974) or by proceduresknown to one skilled in the art.

Step (iii): Conversion of the Compound of Formula A-iii (and itsDisulfide) to the Compound of Formula A (and the Compound of FormulaA-iv):

The thiol compound of formula A-iii as obtained in the above step (ii),(wherein R₅ is as defined herein above; R₇ represents COOH; and Xrepresents halogen, preferably Br) and its disulfide may be esterifiedby refluxing with an appropriate alcohol such as methanol in thepresence of a mineral acid such as sulphuric acid or hydrochloric acidor by any other standard method known in the art, for example, treatingthe compound of formula A-iii with thionyl chloride and an appropriatealcohol such as methanol, to obtain the corresponding ester of generalformula A (wherein R₅ is as defined herein above; R₇ represents alkylcarboxylate; and X represents halogen, preferably Br) along with itsdimer ester of the general formula A-iv. The most preferred method mayinvolve treating the mixture of the compound of formula A-iii and itsdimer in a solvent such as methanol with a mixture of 15% MeOH-conc.H₂SO₄ added dropwise under reflux and with stirring for a time period of6 h to 24 h.

The aryl disulfide ester of the general formula A-iv may be converted tothe compound of general formula A using a reported procedure (Synthesis,59, 1974), more specifically it involves the reduction of compound offormula A-iv using triphenylphosphine or sodium borohydride or sodiumcyanoborohydride etc, at an ambient temperature with stirring for a timeperiod of 15 h in a protic solvent mixture such as methanol:water(4:1v/v) and it may be further processed in a manner known to oneskilled in the art.

Process 6-1: Preparation of Compounds of the General Formula B: Step(i): Preparation of Compound of Formula B-ii:

The hydroxy group in an appropriately substituted o-cresol of generalformula B-i (wherein R₄ is as defined herein above) may be protectedusing any standard procedure known in the art. Thus, the compound ofgeneral formula B-i may be treated with a suitable hydroxy protectingreagent, to obtain the corresponding hydroxy protected derivative ofgeneral formula B-ii (wherein R₄ is as defined herein above). Suitableexamples of hydroxy protecting reagent are: acetyl chloride, aceticanhydride, benzoyl chloride, benzoic anhydride, benzyl chloroformate,hexamethyldisilazane, trimethylsilyl chloride, t-butyldimethylsilylchloride etc. According to the present invention, preferred protectinggroups are acetyl or t-butyldimethyl silyl group, more preferably,t-butyldimethyl silyl group. Accordingly, the compound of formula B-imay be treated with t-butyl dimethylsilyl chloride, to obtain thet-butyldimethylsilyloxy derivative of general formula B-ii (wherein R₄is as defined herein above) in accordance with methods known in the art

Step (ii): Conversion of the Compound of Formula B-ii to the Compound ofFormula B:

The compound of formula B-ii, as obtained in the above step-i (whereinR₄ is as defined herein above) may be treated with a conventionalhalogenating reagent known in the art so that the methyl group in thecompound of formula B-ii is converted to a methyl halide group. Thus,the compound of formula B-ii may be subjected to a halogenation reactionin accordance with methods known in the art which involves treating thesaid compound with a suitable halogenating agent, such asN-bromosuccinimide (NBS) in the presence of an oxidising agent, such asbenzoyl peroxide or 2,2-azobisisobutyronitrile (AIBN) in a solvent suchas CCl₄, over a time period of 2 h to 24 h, to obtain the compound ofgeneral formula B (wherein R₄ is as defined herein above; X representshalogen, preferably Br; and L represents t-butyldimethyl silyloxygroup).

Process 6-2: Preparation of the Compound of Formula B from the Compoundof Formula G-i:

The compound of general formula B (wherein R₄ is as defined hereinabove; X represents halogen, preferably Br; and L represents NO₂) mayalso be synthesized by subjecting an appropriately substituted compoundof general formula G-i (wherein R₄ is as defined herein above) tohalogenation in a manner similar to that described in Process 6-1-Step(ii).

Process 7: Preparation of a Compound of the General Formula (1a′)

wherein U is C(O), CHOH or CH₂; R₂, R₄, R₅ and R₇ are as defined above,comprises subjecting a compound of formula M:

wherein R₂, R₄, R₅ and R₇ are as defined above, to oxidation processusing any standard procedure known in the art. Compound M can beprepared by the reported procedure (J. Med. Chem., 21, 10, 1035,(1978)). The resultant compound may be subjected to standard reductionprocesses to obtain compounds of formula (1a′) wherein U is CHOH or CH₂;R₂, R₄, R₅ and R₇ are as defined above.

It will be appreciated by those skilled in the art that the compounds ofthe present invention may also be utilized in the form of theirpharmaceutically acceptable salts or solvates thereof. Thepharmaceutically acceptable salts of the compounds of the presentinvention are in particular salts which are non-toxic, or which can beused physiologically.

Thus, when the compounds of the present invention represented by thegeneral formula (1) or (1′), more particularly by the general formula(1a) or (1a′) contain one or more basic groups, i.e. groups which can beprotonated, they can form an addition salt with a non-toxic inorganic ororganic acid. Examples of suitable inorganic acids include: boric acid,perchloric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid,sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and otherinorganic acids known to the person skilled in the art. Examples ofsuitable organic acids include: acetic acid, propionic acid, succinicacid, glycolic acid, stearic acid, lactic acid, malic acid, tartaricacid, citric acid, ascorbic acid, pamoic acid, maleic acid,hydroxymaleic acid, fumaric acid, phenylacetic acid, glutamic acid,benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid,toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, ketoglutaric acid,glycerophosphoric acid, aspartic acid, picric acid, lauric acid,palmitic acid, cholic acid, pantothenic acid, alginic acid, naphthoicacid, mandelic acid, tannic acid, camphoric acid and other organic acidsknown to the person skilled in the art.

Thus, when the compounds of the present invention represented by thegeneral formula (1) or (1′), more particularly by the general formula(1a) or (1a′) contain an acidic group they can form an addition saltwith a suitable base. For example, such salts of the compounds of thepresent invention may include their alkali metal salts such as Li, Na,and K salts, or alkaline earth metal salts like Ca, Mg salts, oraluminium salts, or salts with ammonia or salts of organic bases such aslysine, arginine, guanidine, diethanolamine, choline, tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from the subject compound, which contains a basic or anacidic moiety, by conventional chemical methods. Generally the salts areprepared by contacting the free base or acid with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidor base in a suitable solvent or dispersant or from another salt bycation or anion exchange. Suitable solvents are, for example, ethylacetate, ether, alcohols, acetone, THF, dioxane or mixtures of thesesolvents.

The present invention furthermore includes all solvates of the compoundsof the formula (1) or (1′), more particularly of the formula (1a) or(1a′) for example hydrates, and the solvates formed with other solventsof crystallization, such as alcohols, ethers, ethyl acetate, dioxane,DMF, or a lower alkyl ketone, such as acetone, or mixtures thereof.

The present invention also includes all the derivatives of the compoundsof formula (1) or (1′), more particularly of the general formula (1a) or(1a′), for example the esters, prodrugs and other physiologicallyacceptable derivatives.

Various polymorphs of compounds of general formula (1) or (1′), moreparticularly of the general formula (1a) or (1a′), forming part of thisinvention may be prepared by crystallization of compounds of formula E2,(1), (1′), (1a) or (1a′), under different conditions. The differentconditions are, for example, using different commonly used solvents ortheir mixtures for crystallization; crystallization at differenttemperatures; various modes of cooling, ranging from very fast to veryslow cooling during crystallizations. Polymorphs may also be obtained byheating or melting the compound followed by gradual or fast cooling. Thepresence of polymorphs may be determined by IR spectroscopy, solid probeNMR spectroscopy, differential scanning calorimetry, powder X-raydiffraction or such other techniques.

With respect to the compounds of formula (1) or (1′), more particularlyto the compounds of the general formula (1a) or (1a′), the presentinvention also includes all stereoisomeric forms and mixtures thereof inall ratios and their pharmaceutically acceptable salts.

The present compounds are TNF-α inhibitors and find use in therapies fordisorders associated with abnormal TNF-α activity, comprising:inflammatory bowel disease, inflammation, rheumatoid arthritis, juvenilerheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractoryrheumatoid arthritis, chronic non-rheumatoid arthritis,osteoporosis/bone resorption, Crohn's disease, septic shock, endotoxicshock, atherosclerosis, ischemia-reperfusion injury, coronary heartdisease, vasculitis, amyloidosis, multiple sclerosis, sepsis, chronicrecurrent uveitis, hepatitis C virus infection, malaria, ulcerativecolitis, cachexia, psoriasis, plasmocytoma, endometriosis, Behcet'sdisease, Wegener's granulomatosis, meningitis, AIDS, HIV infection,autoimmune disease, immune deficiency, common variable immunodeficiency(CVID), chronic graft-versus-host disease, trauma and transplantrejection, adult respiratory distress syndrome, pulmonary fibrosis,recurrent ovarian cancer, lymphoproliferative disease, refractorymultiple myeloma, myeloproliferative disorder, diabetes, juvenilediabetes, ankylosing spondylitis, and skin delayed-type hypersensitivitydisorders, Alzheimer's disease, systemic lupus erythematosus, allergicasthma.

The present compounds are also interleukin (IL-1, IL-6, IL-8) inhibitorsand find use in therapies for disorders associated with abnormalinterleukin (IL-1, IL-6, IL-8) activity, comprising: rheumatoidarthritis, osteoarthritis and other autoimmune conditions.

The term ‘treating”, “treat” or “treatment” as used herein includespreventive (prophylactic) and palliative treatment.

By “pharmaceutically acceptable” is meant that the carrier, diluent,excipients, and/or salt must be compatible with the other ingredients ofthe formulation, and not deleterious to the recipient thereof.

The expression “prodrug” refers to compounds that are drug precursors,which following administration, release the drug in vivo via somechemical or physiological process e.g., a prodrug on being brought tothe physiological pH or through an enzyme action is converted to thedesired drug form.

A primary aspect of this invention is a method for treating a mammal(e.g., a human) having a disease or condition with underlying TNF-αinvolvement by administering a therapeutically effective amount of acompound of the general formula (1) or (1′), more particularly by thegeneral formula (1a) or (1a′), or a prodrug thereof, or apharmaceutically acceptable salt of the compound or of the prodrug tothe mammal.

Another aspect of this invention is directed to a method for preventingand/or minimizing damage resulting from abnormal TNF-α activity, byadministering to an affected mammal, (e.g., a female or male human), atherapeutically effective amount of a compound of the general formula(1) or (1′), more particularly of the general formula (1a) or (1a′), ora prodrug thereof, or a pharmaceutically acceptable salt of the compoundor the prodrug.

In another aspect of this invention a compound of general formula (1a)or (1a′), is administered locally.

The present invention also envisages the use of a compound of thegeneral formula (1) or (1′), more particularly of the general formula(1a) or (1a′), a prodrug thereof, or a pharmaceutically acceptable saltof the compound or of the prodrug in combination with otherpharmaceutically active compounds. For instance, a pharmaceuticalcomposition, comprising a compound of the general formula (1) or (1′),more particularly of the general formula (1a) or (1a′), or apharmaceutically acceptable salt or prodrug thereof, can be administeredto a mammal, in particular a human, with any other TNF-α inhibitor orany other pharmaceutically active compound known to be useful intreating one of the above mentioned disorders, in mixtures with oneanother or in the form of pharmaceutical preparations.

The present invention furthermore relates to pharmaceutical compositionsthat contain an effective amount of at least one compound of the generalformula (1) or (1′), more particularly of the general formula (1a) or(1a′), and/or its physiologically tolerable salts and/or its prodrugs inaddition to a customary pharmaceutically acceptable carrier, and to aprocess for the production of a pharmaceutical, which comprises bringingat least one compound of formula (1a) or (1a′), into a suitableadministration form using a pharmaceutically suitable andphysiologically tolerable excipient and, if appropriate, furthersuitable active compounds, additives or auxiliaries.

The present invention also relates to a method for the preparation of amedicament for the treatment or prevention of disorders associated withincreased TNF-α activity characterized in that at least one compound ofthe general formula (1) or (1′), more particularly of the generalformula (1a) or (1a′), is used as the pharmaceutically active substance.

The compounds of the present invention are particularly useful asanti-inflammatory agents. The present invention accordingly relates tothe use of a compound of the general formula (1), (1′), (1a) or (1a′),where provisos (ii) and (iii) in formula (1′) are not applicable, forthe manufacture of a medicament for the prevention or treatment ofinflammation.

The compounds of the present invention are also useful for the treatmentof rheumatoid arthritis. The present invention accordingly relates tothe use of a compound of the general formula (1), (1′), (1a) or (1a′),for the manufacture of a medicament for the prevention or treatment ofrheumatoid arthritis, juvenile rheumatoid arthritis, psoriaticarthritis, osteoarthritis, refractory rheumatoid arthritis, chronicnon-rheumatoid arthritis, osteoporosis/bone resorption.

In the methods of treatment using the pharmaceutical compositionsdescribed above, the following are preferred administration routes,modes, etc.

The pharmaceuticals can be administered orally, for example in the formof pills, tablets, coated tablets, capsules, granules or elixirs.Administration, however, can also be carried out rectally, for examplein the form of suppositories, or parenterally, for exampleintravenously, intramuscularly or subcutaneously, in the form ofinjectable sterile solutions or suspensions, or topically, for examplein the form of solutions or transdermal patches, or in other ways, forexample in the form of aerosols or nasal sprays.

The pharmaceutical preparations according to the invention are preparedin a manner known per se and familiar to one skilled in the art.Pharmaceutically acceptable inert inorganic and/or organic carriersand/or additives can be used in addition to the compound(s) of thegeneral formula (1), (1′), (1a) or (1a′), and/or its (their)physiologically tolerable salts and/or its (their) prodrugs. For theproduction of pills, tablets, coated tablets and hard gelatin capsulesit is possible to use, for example, lactose, corn starch or derivativesthereof, gum arabica, magnesia or glucose, etc. Carriers for softgelatin capsules and suppositories are, for example, fats, waxes,natural or hardened oils, etc. Suitable carriers for the production ofsolutions, for example injection solutions, or of emulsions or syrupsare, for example, water, physiological sodium chloride solution oralcohols, for example, ethanol, propanol or glycerol, sugar solutions,such as glucose solutions or mannitol solutions, or a mixture of thevarious solvents which have been mentioned.

The pharmaceutical preparations normally contain about 1 to 99%,preferably about 5 to 70%, most preferably from about 10 to about 30% byweight of the compounds of the formula (1a) or (1a′), and/or theirphysiologically tolerable salts and/or their prodrugs. The amount of theactive ingredient of the formula (1a) or (1a′), and/or itsphysiologically tolerable salts and/or its prodrugs in thepharmaceutical preparations normally is from about 5 to 500 mg. The doseof the compounds of this invention, which is to be administered, cancover a wide range. The dose to be administered daily is to be selectedto suit the desired effect. About 20 to 1,000 mg are preferablyadministered daily per patient. A preferred dosage is about 0.001 to 100mg/kg/day of the compound of formula (1a) or (1a′), or a prodrugthereof. An especially preferred dosage is about 0.01 to 50 mg/kg/day ofa compound of formula (1a) or (1a′), a prodrug thereof, or apharmaceutically acceptable salt of the compound or of the prodrug. Ifrequired, higher or lower daily doses can also be administered. Actualdosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient, which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compounds employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

In addition to the active ingredients of the general formula (1), (1′),(1a) or (1a′), and/or their physiologically acceptable salts and/orprodrugs and carrier substances, the pharmaceutical preparations cancontain additives such as, for example, fillers, antioxidants,dispersants, emulsifiers, defoamers, flavors, preservatives,solubilizers or colorants. They can also contain two or more compoundsof the general formula (1), (1′), (1a) or (1a′), and/or theirphysiologically tolerable salts and/or their prodrugs. Furthermore, inaddition to at least one compound of the general formula (1), (1′), (1a)or (1a′), and/or its physiologically tolerable salts and/or itsprodrugs, the pharmaceutical preparations can also contain one or moreother therapeutically or prophylactically active ingredients.

It is understood that modifications that do not substantially affect theactivity of the various embodiments of this invention are includedwithin the invention disclosed herein. Accordingly, the followingexamples are intended to illustrate but not to limit the presentinvention.

The invention is explained in detail in the examples given below andshould not be construed to limit the scope of the invention:

It is understood that modifications that do not substantially affect theactivity of the various embodiments of this invention are includedwithin the invention disclosed herein. Accordingly, the followingexamples are intended to illustrate but not to limit the presentinvention.

The invention is explained in detail in the examples given below andshould not be construed to limit the scope of the invention:

The following abbreviations are used herein:

-   -   DMF: N,N-dimethylformamide    -   DMSO: dimethylsulfoxide    -   THF: tetrahydrofuran    -   Pet. ether: petroleum ether    -   HBr: hydrogen bromide    -   HCl: hydrochloric acid

Example 12-Amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester

A solution of compound of Example 1j (38 g, 0.75 mol) in DMF (500 mL)was added to a suspension of activated Raney Ni (22 g) in DMF (50 mL)and was subjected to hydrogenation (100 psi pressure and 25° C.) for 4h. The reaction mixture was filtered through celite bed and concentratedunder vacuum. Chloroform (400 mL) was added to the residue withstirring. The crystalline solid obtained was filtered and washed withchloroform, dried to obtain the title compound. Yield: 29 g, (92.45%);mp: 258-260° C.; ¹H NMR (DMSO-d₆, 300 MHz): δ 2.60 (s, 3H, CH₃), 3.85(s, 3H, OCH₃), 5.07 (s, 2H, CH₂), 5.64 (s, 2H, NH₂), 6.61 (d, 2H, Ar),8.06 (s, 1H, Ar), 8.12 (s, 1H, Ar); MS: m/e (ES+) 368 (M+1); analysis:C₁₆H₁₄ClNO₆S requires C, 52.25, H, 3.84; N, 3.81, Cl, 9.64, S 8.72;found: C, 52.37, H, 3.75; N, 3.26, Cl, 9.87, S 8.95%.

Example 1a 4-Amino-3-methyl-benzoic acid

To a solution of 3-methyl-4-nitro-benzoic acid (100 g, 0.55 mol) in DMF(500 mL), suspension of activated Raney Ni (50 g) in DMF (50 mL) wasadded and was subjected to hydrogenation (200 psi pressure and 25° C.)for 6 h. The reaction mixture was filtered through celite bed and wasconcentrated to one third of the total volume. The reaction mixture waspoured into water (1300 mL) with stirring. The solid was filtered,washed with water and dried to obtain the title compound. Yield: 70 g(84%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.03 (s, 3H, CH₃), 5.60 (s, 2H,NH₂), 6.56 (d, 1H, Ar), 7.46 (d, 1H, Ar), 7.49 (s, 1H, Ar); MS: m/e(ES−) 150 (M−1).

Example 1b 4-Bromo-3-methyl-benzoic acid

A suspension of compound of Example 1a (73 g, 0.483 mol) in water (411mL) and 47% HBr (486 mL) was stirred at 25° C. for 1 h and then thereaction mixture was cooled to −2° C. A solution of sodium nitrate (32g, 0.463 mol) in water (100 mL) was added to the reaction mixture over aperiod of 15 min, maintaining the temperature at −1° C. to −2° C. Thereaction mixture was stirred at −1° C. to −2° C. for 1.5 h. The reactionmixture was added slowly to a suspension of copper(I) bromide (73 g,0.508 mol) in water (73 mL) and aqueous HBr (73 mL). The reactionmixture was stirred at 25° C. for 1 h and then digested at 70° C. for 1h. The solid was filtered, washed with water till the pH of the filtratewas 7 and dried to obtain the title compound. Yield: 94 g (90%); ¹H NMR(DMSO-d₆, 300 MHz): δ 2.37 (s, 3H, CH₃), 7.64 (m, 2H, Ar), 7.87 (s, 1H,Ar); MS: m/e (ES−) 214 (M−1).

Example 1c 4-Bromo-3-chlorosulfonyl-5-methyl-benzoic acid

Chlorosulfonic acid (150 mL, 2.18 mol) was added slowly to compound ofExample 1b (74 g, 0.344 mol) at 0° C. The reaction mixture was refluxedfor 4.5 h and then was poured into ice-cold water (1500 mL) withstirring. The solid was filtered, washed with water till filtrate wasneutral and dried to obtain the title compound. Yield: 72.40 g (66.8%);¹H NMR (DMSO-d₆, 300 MHz): δ 2.40 (s, 3H, CH₃), 7.80 (s, 1H, Ar), 8.30(s, 1H, Ar); MS: m/e (ES−) 315 (M−1).

Example 1d Dimer of 4-Bromo-3-mercapto-5-methyl-benzoic acid

A solution of stannous chloride (196 g, 0.86 mol) in concentratedhydrochloric acid (250 mL) and water (55 mL) was added to a stirredsuspension of compound of Example 1c (68 g, 0.217 mol) in acetic acid(580 mL) at 80° C., over a period of 20 min. The reaction mixture wasstirred at 80° C. for 4 h. The reaction mixture was cooled, poured intowater (500 mL) with stirring and digested at 80° C. for 30 min. Thesolid was filtered, washed with water till filtrate was neutral anddried to obtain the title compound. Yield: 48 g (90%); ¹H NMR (DMSO-d₆,300 MHz): δ 2.40 (s, 3H, CH₃), 7.70 (s, 1H, Ar), 7.84 (s, 1H, Ar); MS:m/e (ES−) 491 (M−1).

Example 1e Dimer of 4-bromo-3-mercapto-5-methyl-benzoic acid methylester

Thionyl chloride (130 mL, 1.82 mol) was added slowly to the compound ofExample 1d (48 g, 0.198 mol) at 0° C. The reaction mixture was refluxedfor 18 h. Excess thionyl chloride was distilled out from the reactionmixture. The reaction mixture was cooled to 0° C. and methanol (200 mL)was added slowly over a period of 15 min. The reaction mixture wasrefluxed for 1 h. Methanol was removed from the reaction mixture underreduced pressure, and water (500 mL) was added and stirred for 15 min.The solid precipitated was filtered, washed with water and dried toobtain the title compound. Yield: 47 g (93%); ¹H NMR (DMSO-d₆, 300 MHz):δ 2.42 (s, 3H, CH₃), 3.77 (s, 3H, OCH₃), 7.78 (s, 1H, Ar), 7.89 (s, 1H,Ar); MS: m/e (EI) 520 (M+).

Example 1f 4-Bromo-3-mercapto-5-methyl-benzoic acid methyl ester

Triphenyl phosphine (34 g, 0.126 mol) was added to a suspension ofcompound of Example 1e (47 g, 0.09 mol) in methanol (1000 mL) and water(300 mL). The reaction mixture was stirred at 25° C. for 2 h. Methanolwas removed under reduced pressure, water (500 mL) was added andextracted using ethyl acetate (3×300 mL). The combined organic layer waswashed with water (300 mL), brine (200 mL), dried and purified by columnchromatography (silica gel, 1% ethyl acetate in pet. ether 60-80° C.) toobtain the title compound. Yield: 43 g (92%); ¹H NMR (CDCl₃, 300 MHz): δ2.44 (s, 3H, CH₃), 3.89 (s, 3H, OCH₃), 4.07 (s, 1H, SH), 7.63 (s, 1H,Ar), 7.84 (s, 1H, Ar); MS: m/e (ES−) 260 (M−1).

Example 1g4-Bromo-3-[2-(tert-butyl-dimethyl-silanyloxy)-3-chloro-benzylsulfanyl]-5-methyl-benzoicacid methyl ester

Triethyl amine (36 mL, 0.263 mol) was added to a solution of(2-bromomethyl-6-chloro-phenoxy)-tert-butyl-dimethyl-silane (72 g, 0.214mol) [prepared from 6-chloro cresol by protecting the hydroxy group witht-butyldimethylsilane followed by bromination using N-bromosuccinimide]and compound of Example 1f (43 g, 0.164 mol) in chloroform (600 mL) at5° C. over a period of 20 min. The reaction mixture was stirred at 25°C. for 30 min. The reaction mixture was washed with water (2×200 mL) andbrine (100 mL). The solvent was removed under reduced pressure and tothe oily mass obtained, methanol (300 mL) was added with stirring. Thecrystalline solid obtained was filtered, washed with methanol and driedto obtain the title compound. Yield: 70 g, (83%); ¹H NMR (CDCl₃, 300MHz): δ 0.28 (s, 6H, 2CH₃), 1.03 (s, 9H, 3CH₃), 2.45 (s, 3H, CH₃), 3.89(s, 3H, OCH₃), 4.19 (s, 2H, CH₂), 6.89 (t, 1H, Ar), 7.24 (t, 1H, Ar),7.32 (d, 1H, Ar), 7.61 (s, 1H, Ar), 7.69 (s, 1H, Ar); MS: m/e (ES−) 515(M−1).

Example 1h 4-Bromo-3-[2-(tert-butyl-dimethyl-silanyloxy)-3-chloro-phenylmethane sulfonyl]-5-methyl-benzoic acid methyl ester

m-Chlorobenzoic acid (127 g, 0.33 mol) was added in three portions at aninterval of 10 min to a solution of compound of Example 1g (70 g, 0.135mol) in dichloromethane (700 mL) at 15° C. and stirred further at 25° C.for 16 h. The reaction mixture was filtered. The solvent was removedfrom the filtrate under reduced pressure and the residue was stirred insaturated bicarbonate solution (2×200 mL). The solid was filtered,washed with water and dried to obtain the title compound. Yield: 72.8 g(97%); ¹H NMR (CDCl₃, 300 MHz): δ 0.22 (s, 6H, 2CH₃), 0.99 (s, 9H,3CH₃), 2.56 (s, 3H, CH₃), 3.89 (s, 3H, OCH₃), 4.75 (s, 2H, CH₂), 6.81(t, 1H, Ar), 7.13 (d, 1H, Ar), 7.26 (d, 1H, Ar), 8.11 (s, 1H, Ar), 8.29(s, 1H, Ar); MS: m/e (CI) 549 (M+1).

Example 1i4-Chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

A solution of tetrabutyl ammonium fluoride (90 g, 0.283 mol) intetrahydrofuran (250 mL) was added dropwise to a solution of compound ofExample 1h (72 g, 0.135 mol) in tetrahydrofuran (350 mL) over a periodof 25 min under nitrogen, at 5° C. The reaction mixture was stirred at5° C. for 30 min. Solvent was removed under reduced pressure and water(250 mL) was added. The solid was filtered and washed with water (2000mL). The crude product was purified by column chromatography (silicagel, methanol in chloroform) to obtain the title compound. Yield: 37.0 g(87%); ¹H NMR (CDCl₃, 300 MHz): δ 2.71 (s, 3H, CH₃), 3.91 (s, 3H, OCH₃),4.72 (s, 2H, CH₂), 7.25 (d, 1H, Ar), 7.33 (d, 1H, Ar), 7.45 (d, 1H, Ar),8.09 (s, 1H, Ar), 8.46 (s, 1H, Ar); MS: m/e (EI) 352 (M+).

Example 1j4-Chloro-6-methyl-2-nitro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

Concentrated sulfuric acid (240 mL, 4.2 mol) was added to a solution ofcompound of Example 11 (37 g, 0.105 mol) in concentrated nitric acid(1100 mL, 17.34 mol) at 5° C. The reaction mixture was stirred at 5° C.for 25 min, and then at 40° C. for 4.5 h. Reaction mixture was quenchedinto ice water (2500 mL), the solid precipitated was filtered, washedwith water till filtrate was neutral to pH and dried to obtain the titlecompound. Yield: 38 g (90.91%); ¹H NMR (CDCl₃, 300 MHz): δ 2.7 (s, 3H,CH₃), 3.90 (s, 3H, OCH₃), 4.79 (s, 2H, CH₂), 8.10 (s, 1H, Ar), 8.22 (s,1H, Ar), 8.38 (s, 1H, Ar), 8.48 (s, 1H, Ar); MS: m/e (ES−) 396 (M−1).

Example 22-Amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid

A solution of sodium hydroxide (0.32 g, 7.13 mmol) in water (5 mL) wasadded to a solution of Example 1 (1 g, 2.71 mmol) in methanol (30 mL).The reaction mixture was stirred at 60° C. for 1.5 h, the solvent wasremoved under vacuum and water (20 mL) was added. The reaction mixturewas acidified to pH 3 using 10% aqueous hydrochloric acid. Theprecipitate was filtered and washed with water, dried to obtain thetitle compound. Yield: 0.85 g, (89%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.61(s, 3H, CH₃), 5.66 (s, 2H, CH₂), 6.64 (d, 2H, Ar), 8.03 (s, 1H, Ar),8.12 (s, 1H, Ar); MS: m/e (ES−) 352 (M−1).

Example 32-Amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid sodium salt

A solution of sodium hydroxide (0.018 g, 0.47 mmol) in water (0.2 mL)was added to a solution of Example 2 (0.167 g, 0.47 mmol) in methanol (5mL) and stirred at 25° C. for 15 min. The solvent was removed undervacuum, and dried to obtain the title compound. Yield: 0.16 g, (91%); ¹HNMR (DMSO-d₆, 300 MHz): δ 2.55 (s, 3H, CH₃), 4.92 (s, 2H, CH₂), 5.57 (s,2H, NH₂), 6.60 (m, 2H, Ar), 7.90 (s, 1H, Ar), 8.10 (s, 1H, Ar); MS: m/e(ES−) 352 (M−Na); analysis: C₁₅H₁₁ClNNaO₅S.2H₂O requires C, 43.75, H,3.67; N, 3.40, Cl, 8.61, S, 7.79; found: C, 44.20, H, 3.34; N, 3.49, Cl,9.25, S, 8.36%.

Example 44-Chloro-2-(2-chloro-acetylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

Chloroacetylchloride (3.3 mL, 40.8 mmol) was added to the solution ofcompound of Example 1 (5 g, 13.6 mmol) in dichloromethane (100 mL) at20° C. Pyridine (6.6 mL, 81.6 mmol) was added and the reaction mixturewas stirred for 2 h. The solvent was removed under vacuum and water (200mL) was added. The solid obtained was filtered, washed with water andpurified by stirring in ethyl acetate (200 mL) at reflux condition for30 min. The solid was filtered and dried to obtain the title compound.Yield: 4.86 g (80.1%); mp 292-293° C.; ¹H NMR (DMSO-d₆, 300 MHz): δ 2.64(s, 3H, CH₃), 3.86 (s, 3H, OCH₃), 4.27 (s, 2H, CH₂), 5.34 (s, 2H, CH₂),7.67 (s, 1H, Ar), 7.88 (s, 1H, Ar), 8.11 (s, 1H, Ar), 8.15 (s, 1H, Ar),10.70 (s, 1H, NH); MS: m/e (ES+) 445 (M+1); analysis: C₁₈H₁₅Cl₂NO₆Srequires C, 48.66, H, 3.40; N, 3.15, Cl, 15.96, S, 7.22; found: C,48.09, H, 3.37; N, 3.38, Cl, 16.37, S, 7.72%.

Example 54-Chloro-2-(2-hydroxy-acetylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester (A)

2-(2-Acetoxy-acetylamino)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester (B) Sodium acetate (0.054 g, 0.658 mmol) in water (5mL) was added to solution of compound of Example 4 (0.18 g, 0.405 mmol)in DMF (5 mL) at 25° C. and then the reaction mixture was stirred at 80°C. for 6 h. The solvent was removed under vacuum, water (15 mL) wasadded and extracted using ethyl acetate (3×30 mL). Combined organiclayer was washed with water (2×100 mL), brine (100 mL) and dried overanhydrous sodium sulfate. The solvent was removed under vacuum and crudeproduct was purified by column chromatography (silica gel) to obtain thetitle compound (B) (1% methanol in chloroform) and compound (A) (2%methanol in chloroform).

Compound (A): Yield: 0.05 g; mp 276-278° C.; ¹H NMR (DMSO-d₆, 300 MHz):δ 2.65 (s, 3H, CH₃), 3.68 (s, 3H, OCH₃), 4.0 (d, 2H, CH₂), 5.28 (s, 2H,CH₂), 5.68 (t, 1H, OH), 7.90 (s, 1H, Ar), 7.96 (s, 1H, Ar), 8.11 (s, 1H,Ar), 8.15 (s, 1H, Ar), 10.08 (s, 1H, NH); MS: m/e (ES−) 424 (M−1);analysis: C₁₈H₁₆ClNO₇S requires C, 50.77, H, 3.79; N, 3.29, Cl, 8.33, S,7.53; found: C, 49.86, H, 3.80; N, 3.23, Cl, 8.72, S, 7.12%.

Compound (B): Yield: 0.030 g; mp:180-182° C.; ¹H NMR (DMSO-d₆, 300 MHz):δ 2.09 (s, 3H, CH₃), 2.63 (s, 3H, CH₃), 3.84 (s, 3H, OCH₃), 4.64 (s, 2H,CH₂), 5.29 (s, 2H, CH₂), 7.67 (d, 1H, Ar), 7.83 (s, 1H, Ar), 8.09 (d,1H, Ar), 8.14 (d, 1H, Ar); MS: m/e (ES+) 468 (M+1); analysis:C₂₀H₁₈ClNO₈S requires C, 51.34, H, 3.88; N, 2.99, Cl, 7.58, S, 6.85;found: C, 49.30, H, 3.79; N, 2.80, Cl, 7.63, S, 6.40%.

Example 64-Chloro-6-methyl-10,10-dioxo-2-propionylamino-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

A solution of oxalyl chloride (0.17 mL, 2.03 mmol) and propionic acid(0.15 mL, 2.03 mmol) in dichloromethane (20 mL) was stirred for 1 h.Compound of Example 1 (0.5 g, 1.35 mmol) in DMF (5 mL) was added to thereaction mixture at 25° C. and stirred for 18 h. The solvent was removedunder vacuum, water (25 mL) was added and the solid precipitated wasfiltered. The crude product was purified by column chromatography(silica gel, 1% methanol in chloroform) to obtain the title compound.Yield: 0.28 g, (60%); mp: 226-228° C.; ¹H NMR (DMSO-d₆, 300 MHz): δ 1.06(t, 3H, CH₃), 2.33 (q, 2H, CH₂), 2.64 (s, 3H, CH₃), 3.85 (s, 3H, OCH₃),5.30 (s, 2H, CH₂), 7.66 (d, 1H, Ar), 7.88 (s, 1H, Ar), 8.10 (s, 1H, Ar),8.15 (s, 1H, Ar), 10.26 (s, 1H, NH); MS: m/e (EI) 423 (M+); analysis:C₁₉H₁₈ClNO₆S requires C, 53.66, H, 4.28; N, 3.30, Cl, 8.32, S, 7.56;found: C, 53.38, H, 4.27; N, 3.48, Cl, 8.64, S, 7.75%.

Example 74-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid

Sodium formate (0.308 g, 4.58 mmol) was added to a solution of compoundof Example 2 (0.8 g, 2.26 mmol) in formic acid 85% (8 mL) and refluxedfor 2 h. The reaction mixture was diluted using water (20 mL) and thesolid obtained was filtered, washed with water and dried. The productwas purified by crystallisation using DMF/methanol to obtain the titlecompound. Yield: 0.78 g, (91%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.64 (s,3H, CH₃), 5.31 (s, 2H, CH₂), 7.70 (s, 1H, Ar), 7.87 (s, 1H, Ar), 7.93(s, 1H, Ar), 8.08 (s, 1H, Ar), 8.31 (s, 1H, CHO), 10.57 (s, 1H, NH); MS:m/e (ES−) 380 (M−1);

Example 84-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid sodium salt

A solution of sodium hydroxide (0.0108 g, 0.27 mmol) in water (0.1 mL)was added to the solution of Example 7 (0.104 g, 0.27 mmol) in methanol(5 mL) and stirred at 25° C. for 15 min, the solvent was removed anddried to obtain the title compound. Yield: 0.11 g, (100%); ¹H NMR(DMSO-d₆, 300 MHz): δ 2.58 (s, 3H, CH₃), 5.16 (s, 2H, CH₂), 7.69 (d, 1H,Ar), 7.87 (d, 1H, Ar), 7.95 (s, 1H, Ar), 8.11 (s, 1H, Ar), 8.30 (s, 1H,CHO), 10.78 (s, 1H, NH); MS: m/e (ES−) 380 (M−Na); analysis:C₁₆H₁₁ClNNaO₆S.2H₂O requires C, 43.70, H, 3.44; N, 3.81, Cl, 8.06, S,7.29; found: C, 42.88, H, 3.19; N, 3.04, Cl, 8.69, S, 7.67%.

Example 94-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

Sodium formate (7.29 g, 0.108 mol) was added to a suspension of compoundof Example 1 (20 g, 0.054 mol) in formic acid (200 mL) and refluxed for1.5 h. The reaction mixture was cooled and poured into ice water (800mL). The solid precipitated was filtered, washed with water and dried.The crude product was purified by column chromatography (silica gel, 1%methanol in chloroform) to obtain the title compound. Yield: 18 g,(83%); mp 258-262° C. (decomposed); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.64(s, 3H, CH₃), 3.86 (s, 3H, OCH₃), 5.25 (s, 2H, CH₂, trans minor isomer),5.33 (s, 2H, CH₂, cis major isomer), 7.33 (d, 1H, Ar, trans minorisomer), 7.50 (d, 1H, Ar, trans minor isomer), 7.69 (d, 1H, Ar, cismajor isomer), 7.86 (d, 1H, Ar, cis major isomer), 8.10 (s, 1H, Ar),8.15 (s, 1H, Ar), 8.30 (s, 1H, CHO, cis major isomer), 8.80 (d, 1H, CHO,trans minor isomer), 10.40 (d, 1H, NH, trans minor isomer), 10.57 (s,1H, NH, cis major isomer); MS: m/e (ES−) 394 (M−1); analysis:C₁₇H₁₄ClNO₆S requires C, 51.54, H, 3.56; N, 3.54, Cl, 8.96, S, 8.10;found: C, 51.96, H, 3.63; N, 3.60, Cl, 9.43, S, 8.50%.

Example 104-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid ethyl ester

Sodium formate (0.075 g, 1.1 mmol) was added to a suspension of2-amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid ethyl ester (0.420 g, 1.1 mmol) [prepared by hydrolysis of compoundof Example 1 and followed by esterification with ethanol/H₂SO₄] informic acid (25 mL) and refluxed for 1.5 h. The reaction mixture wascooled and poured into ice water (100 mL). The solid precipitated wasfiltered, washed with water and dried. The crude product was purified bycolumn chromatography (silica gel, 1% methanol in chloroform) to obtainthe title compound. Yield: 0.21 g (47%); mp 202-204° C.; ¹H NMR(DMSO-d₆, 300 MHz): δ 1.31 (t, 3H, OCH₂CH₃), 2.64 (s, 3H, CH₃), 4.31 (q,2H, OCH₂CH₃), 5.25 (s, 2H, CH₂, trans minor isomer), 5.33 (s, 2H, CH₂,cis major isomer), 7.34 (d, 1H, Ar, trans minor isomer), 7.50 (d, 1H,Ar, trans minor isomer), 7.69 (d, 1H, Ar, cis major isomer), 7.86 (d,1H, Ar, cis major isomer), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar), 8.31 (s,1H, CHO, cis major isomer), 8.80 (d, 1H, CHO, trans minor isomer), 10.43(d, 1H, NH, trans minor isomer), 10.57 (s, 1H, NH, cis major isomer);MS: m/e (ES−) 408 (M−1); analysis: C₁₈H₁₆ClNO₆S requires C, 52.75, H,3.93; N, 3.42, Cl, 8.65, S, 7.82; found: C, 52.47, H, 3.86; N, 3.36, Cl,8.81, S, 7.67%.

Example 114-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid isopropyl ester

Sodium formate (0.040 g, 0.581 mmol) was added to a suspension of2-amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid isopropyl ester (0.23 g, 0.581 mmol) [prepared by hydrolysis ofcompound of Example 1 and followed by esterification usingisopropanol/H₂SO₄] in formic acid (20 mL) and refluxed for 1.5 h. Thereaction mixture was cooled and poured into ice water (100 mL). Thesolid precipitated was filtered, washed with water and dried. The crudeproduct was crystallised with ethylacetate /pet. ether 60-80° C. toobtain the title compound. Yield: 0.12 g (48%); mp: 212-215° C.; ¹H NMR(DMSO-d₆, 300 MHz): δ 1.30 (d, 6H, OCH(CH₃)₂), 2.64 (s, 3H, CH₃), 5.12(m, 1H, OCH(CH₃)₂), 5.25 (s, 2H, CH₂, trans minor isomer), 5.32 (s, 2H,CH₂, cis major isomer), 7.33 (d, 1H, Ar, trans minor isomer), 7.50 (d,1H, Ar, trans minor isomer), 7.69 (d, 1H, Ar, cis major isomer), 7.86(d, 1H, Ar, cis major isomer), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar), 8.30(s, 1H, CHO, cis major isomer), 8.80 (d, 1H, CHO, trans minor isomer),10.40 (d, 1H, NH, trans minor isomer), 10.57 (s, 1H, NH, cis majorisomer); MS: m/e (ES−) 422 (M−1); analysis: C₁₆H₁₈ClNO₆S requires C,53.84, H, 4.28; N, 3.30, Cl, 8.36, S, 7.56; found: C, 54.27, H, 4.45; N,2.94, Cl, 8.76, S, 7.77%.

Example 122-[Bis-(2-chloro-ethyl)amino]-4-chloro-6-methyl10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylicacid methyl ester

Sodium borohydride (2.90 g, 0.072 mol) was portionwise added to astirred solution of chloroacetic acid (12.08 g, 0.12 mol) in benzene(300 mL) and dry tetrahydrofuran (30 mL) under nitrogen atmosphere at10° C. The reaction mixture was stirred for 1 h till no furtherevolution of hydrogen gas was observed. Compound of Example 1 (4.7 g,0.012 mol) was added to the reaction mixture and the mixture wasrefluxed for 3 h. 10% sodium bicarbonate solution (100 mL) was added tothe reaction mixture and extracted with ethyl acetate (3×100 mL).Combined organic layer was washed with water (2×100 mL), brine (100 mL)and dried over anhydrous sodium sulfate. Solvent was removed undervacuum and the crude product obtained was crystallized using ethylacetate/hexane to obtain the title compound. Yield: 3.30 g (52%); mp:190-191° C.; ¹H NMR (CDCl₃, 300 MHz): δ 2.80 (s, 3H, CH₃), 3.82 (s, 8H,4-CH₂), 3.90 (s, 3H, OCH₃), 5.20 (s, 2H, CH₂), 6.90 (d, 1H, Ar), 7.10(d, 1H, Ar), 8.1 (s, 1H, Ar), 8.45 (s, 1H, Ar); MS: m/e (ES+) 492 (M+1);analysis: C₂₀H₂₀Cl₃NO₆S requires C, 48.75, H, 4.09; N, 2.84, Cl, 21.58;S, 6.51; found: C, 48.75, H, 3.93; N, 2.58, Cl, 21.85; S, 6.73%.

Example 132-[Bis-(2-hydroxy-ethyl)-amino]-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester

Ethylene oxide (120 mL) was added to a stirred solution of compound ofExample 1 (4.5 g, 12.26 mmol) in acetic acid (50 mL), water (50 mL) andTHF (20 mL) mixture at −70° C., over a period of 1 h and then stirred at25° C. for 14 h. The reaction mixture was cooled; pH was adjusted to 7using 10% aqueous solution of sodium bicarbonate. The reaction mixturewas extracted with ethyl acetate (3×250 mL). Combined organic layer waswashed with brine (2×100 mL) and dried over sodium sulphate. Solvent wasremoved and the resulting crude product was purified by columnchromatography (silica gel, ethyl acetate/pet ether) to obtain the titlecompound. Yield: 4 g (72%); mp 199-201° C.; ¹H NMR (DMSO-d₆, 300 MHz): δ2.62 (s, 3H, CH₃), 3.40 (t, 4H, 2CH₂), 3.51 (t, 4H, 2CH₂), 3.85 (s, 3H,OCH₃), 4.80 (t, 2H, 20H), 5.11 (s, 2H, CH₂), 6.76 (s, 1H, Ar), 6.83 (s,1H, Ar), 8.06 (s, 1H, Ar), 8.13 (s, 1H, Ar); MS: m/e (ES+) 456 (M+1).

Example 144-Chloro-6-methyl-2-piperazin-1-yl-11H-5-oxa-10-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester hydrochloride (Compound A) Example 154-Chloro-6-methyl-10-oxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*4*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl esterhydrochloride (Compound B)

Aqueous ammonia solution (25%, 30 mL) was added to2-[bis-(2-chloroethyl)-amino]-4-chloro-6-methyl-10-oxo-10,11-dihydro-5-oxa-10lambda*4*-thia-dibenzo[a,d]-cycloheptene-8-carboxylicacid (3.2 g, 6.9 mmol) [prepared by alkaline hydrolysis of compound ofExample 15e] in methanol (120 mL). The reaction mixture was sealed undernitrogen atmosphere, kept at 110° C. for 9 h, cooled and the seal wasopened. The reaction mixture was concentrated to remove solvent andammonia, and azeotroped with toluene once. The product was taken inmethanolic HCl solution (45 mL) and stirred at 90° C. for 4 h. Thereaction mixture was cooled. The solid separated was filtered, washedwith methanol and dried under vacuum to obtain the crude product. Thecrude product was dissolved in chloroform and treated with aqueoussodium carbonate to obtain the freebase, which was purified by columnchromatography (silica gel, 5% methanol in chloroform) to obtain freebase of compound A (yield: 0.3 g) and free base of compound B (yield:0.25 g).

Free base of compound A and free base of compound B were converted tothe hydrochloride salt using methanolic HCl to obtain title compound A(Example 14) and title compound B (Example 15).

Compound A

Mp: 256-259° C.; ¹H NMR (DMSO-d₆, 300 MHz): δ 2.53 (s, 3H, CH₃), 3.14(s, 4H, 2CH₂), 3.40 (s, 4H, 2CH₂), 3.78 (s, 3H, OCH₃), 4.32 (s, 2H,CH₂), 7.02 (s, 2H, Ar), 7.57 (s, 1H, Ar), 7.58 (s, 1H, Ar) and 9.18 (s,2H, NH & HCl); MS: m/e (ES+) 405 (M+1, free base).

Compound B

Mp: >320° C.; ¹H NMR (DMSO-d₆, 300 MHz): δ 2.58 (s, 3H, CH₃), 3.19 (s,4H, 2CH₂), 3.42 (s, 4H, 2CH₂), 3.89 (s, 3H, OCH₃), 4.73 (d, 2H, CH₂),7.16 (s, 2H, Ar), 8.01 (s, 1H, Ar), 8.12 (s, 1H, Ar) and 9.18 (s, 2H, NH& HCl); MS: m/e (ES+) 421 (M+1, free base).

Example 15a4-Bromo-3-(3-chloro-2-hydroxy-benzylsulfanyl)-5-methyl-benzoic acidmethyl ester

The solution of tetrabutyl ammonium fluoride (42.8 g, 0.13 mol) in THF(350 mL) was added dropwise to a solution of compound of Example 1g (35g, 0.068 mol) in THF (150 mL) under nitrogen at 5° C. and stirred for 30min. Solvent was removed from the reaction mixture and ice water (200mL) was added. The solid separated was filtered, and washed with water(3×100 ml). The crude obtained was purified by column chromatography(silica gel, ethyl acetate/pet. ether) to obtain the title compound.Yield: 24 g, (88%); ¹H NMR (CDCl₃, 300 MHz): δ 2.44 (s, 3H, CH₃), 3.87(s, 3H, OCH₃), 4.26 (s, 2H, CH₂), 6.81 (t, 1H, Ar), 7.20-7.26 (m, 2H,Ar), 6.81 (t, 1H, Ar), 7.70 (s, 1H, Ar); MS: m/e (EI) 401 (M+).

Example 15b4-Chloro-6-methyl-11H-5-oxa-10-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

Sodium hydride (1.65 g, 0.068 mol) was added portionwise to a solutionof compound of Example 15a (23 g, 0.057 mol) in DMF (600 mL) and stirredat 80° C. for 10 h. The solvent was removed, and chloroform (300 mL) wasadded. The organic layer was washed with 10% HCl (2×80 mL), followed bywater (100 mL), and brine and dried over anhydrous sodium sulphate. Thesolvent was removed and the crude product obtained was purified bycolumn chromatography (silica gel, ethyl acetate/pet ether) to obtainthe title compound. Yield: 9 g, (49%); ¹H NMR (CDCl₃, 300 MHz): δ 2.50(s, 3H, CH₃), 3.91 (s, 3H, OCH₃), 4.21 (s, 2H, CH₂), 7.05 (m, 2H, Ar),7.28 (d, 1H, Ar), 7.60 (d, 2H, Ar); MS: m/e (EI) 320 (M+).

Example 15c4-Chloro-6-methyl-2-nitro-10-oxo-10,11-dihydro-5-oxa-10lambda*4*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

Compound of Example 15b (4.1 g, 12.8 mmol) was added to solution ofnitrating mixture (nitric acid 200 mL and sulfuric acid 20 mL) at 0° C.and stirred for 18 h. The reaction mixture was poured slowly withstirring into ice water (200 mL). The solid separated was filtered,washed with water and dried to obtain the title compound. Yield: 2.5 g,(52%); ¹H NMR (CDCl₃, 300 MHz): δ 2.65 (s, 3H, CH₃), 3.93 (s, 3H, OCH₃),4.57 (s, 2H, CH₂), 8.16 (d, 2H, Ar), 8.35 (d, 2H, Ar); MS: m/e (ES−) 380(M−1).

Example 15d2-Amino-4-chloro-6-methyl-10-oxo-10,11-dihydro-5-oxa-10lambda*4*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

The solution of compound of Example 15c (3.7 g, 9.7 mmol) in DMF (100mL) was added to a suspension of activated Raney Nickel (3.7 g) in DMF(10 mL) and was subjected to hydrogenation at 50 psi pressure at 25° C.for 6 h. The reaction mixture was filtered using celite bed and thesolvent was removed. The crude product obtained was purified by columnchromatography (silica gel, methanol/chloroform) to obtain the titlecompound. Yield: 2.5 g, (74%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.56 (s, 3H,CH₃), 3.84 (s, 3H, OCH₃), 4.61 (q, 2H, CH₂), 5.5 (s, 2H, NH₂), 6.61 (s,2H, Ar), 7.97 (s, 1H, Ar); MS: m/e (EI) 351 (M+).

Example 15e2-[Bis-(2-chloroethyl)amino]-4-chloro-6-methyl-10-oxo-10,11-dihydro-5-oxa-10lambda*4*thia-dibenzo[a,d]-cycloheptene-8-carboxylicacid methyl ester

Sodium borohydride (1.48 g, 39.22 mmol) was added portionwise to astirred solution of chloroacetic acid (7.41 g, 78.45 mmol) in benzene(200 mL) and dry THF (20 mL) under nitrogen atmosphere at 10° C. Thereaction mixture was stirred for 1.5 h (till no further evolution ofhydrogen gas was observed) and compound of Example 15d (2.3 g, 6.54mmol) was added, and the reaction mixture was refluxed for 6 h. To thereaction mixture, 10% sodium bicarbonate solution (100 mL) was added andextracted with ethyl acetate (3×200 mL). The combined organic layer waswashed with water (2×100 mL), brine (100 mL) and dried over anhydroussodium sulfate. Solvent was removed and the crude product obtained wascrystallized using ethyl acetate/hexane to obtain the title compound.Yield: 2.6 g (80%); ¹H NMR (CDCl₃, 300 MHz): δ 2.65 (s, 3H, CH₃),3.62-3.66 (m, 4H, 2CH₂), 3.72-3.76 (m, 4H, 2CH₂), 3.90 (s, 3H, OCH₃),4.35 (d, J=12.3 Hz, 1H, CH_(A)H_(B) SO), 4.62 (d, J=12.3 Hz, 1H,CH_(A)H_(B) SO), 6.51 (d, J=2.98 Hz, 1H, Ar), 6.66 (d, J=3.05 Hz, 1H,Ar), 8.02 (d, J=1.47 Hz, 1H, Ar), 8.33 (d, J=1.78 Hz, 1H, Ar); MS: m/e(ES−) 492 (M−1).

Example 164-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylicacid methyl ester hydrochloride

Aqueous ammonia solution (25%, 300 mL) was added to2-[bis-(2-chloroethyl)-amino]-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylicacid (52 g, 0.109 mol) [prepared by alkaline hydrolysis of compound ofExample 12] in methanol (100 mL). The reaction mixture was sealed undernitrogen atmosphere, kept at 110° C. for 9 h, cooled and the seal wasopened. The reaction mixture was concentrated to remove solvent andammonia, and azeotroped with toluene. The product was taken inmethanolic HCl solution (300 mL) and stirred at 70° C. for 9 h. Thereaction mixture was cooled, solid separated was filtered, washed withmethanol and dried under vacuum to obtain the crude product. The crudeproduct was dissolved in chloroform and treated with aqueous sodiumcarbonate to obtain the free base, which was purified by columnchromatography (silica gel, 5% methanol in chloroform) to obtainfreebase of the title compound. Yield: 32 g (68%). This was converted tothe hydrochloride salt using methanolic HCl. mp: 277-280° C.; ¹H NMR(DMSO-d₆, 300 MHz): δ 2.66 (s, 3H, CH₃), 3.19 (m, 4H, 2CH₂), 3.40 (m,4H, 2CH₂), 3.85 (s, 3H, OCH₃), 5.10 (s, 2H, CH₂), 7.10 (s, 1H, Ar), 7.20(s, 1H, Ar), 8.05 (s, 1H, Ar) and 8.20 (s, 1H, Ar); MS: m/e (ES+) 437(M+1, free base); analysis: C₂₀H₂₂Cl₂N₂O₆S requires C, 50.75, H, 4.68;N, 5.92, Cl, 14.98, S, 6.77; found: C, 50.85, H, 4.62; N, 6.14, Cl,15.30, S, 6.80%.

Example 174-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester mesylate

A solution of methane sulfonic acid (0.023 mL, 0.3612 mmol) in methanol(1 mL) was added to a solution of4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester (free base of example 16, 0.15 g, 0.344 mmol) inmethanol (10 mL) at 25° C. and stirred for 15 min. The resultantprecipitate was filtered, washed using methanol and dried to obtain thetitle compound. Yield: 0.13 g, (71%); mp 279-281° C.; ¹H NMR (CDCl₃, 300MHz): δ 2.30 (s, 3H, CH₃), 2.63 (s, 3H, CH₃), 3.22 (s, 4H, 2CH₂), 3.39(s, 4H, 2CH₂), 3.85 (s, 3H, OCH₃), 5.17 (s, 2H, CH₂), 7.18 (s, 1H, Ar),7.20 (s, 1H, Ar), 8.09 (s, 1H, Ar), 8.15 (s, 1H, Ar), 8.72 (s, 2H, NH₂);MS: m/e (ES+) 437 (M+1, free base); analysis: C₂₁H₂₅ClN₂O₈S₂ requires C,47.32, H, 4.73; N, 5.26, Cl, 6.65, S, 12.03; found: C, 47.80, H, 4.93;N, 5.44, Cl, 7.07, S, 11.75%.

Example 184-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid

A solution of sodium hydroxide (0.22 g, 5.49 mmol) in water (15 mL) wasadded to a solution of4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester (free base of example 16, 0.88 g, 1.83 mmol) intetrahydrofuran (25 mL). The reaction mixture was stirred at 40° C. for4 h, the solvent was removed under vacuum. The reaction mixture wasacidified to pH 4-5 using 10% aqueous hydrochloric acid. The precipitatewas filtered, washed with water and dried to obtain the title compound.Yield: 0.84 g, (98%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.65 (s, 3H, CH₃),3.26 (s, 4H, 2CH₂), 3.43 (s, 4H, 2CH₂), 5.16 (s, 2H, CH₂), 7.20 (s, 2H,Ar), 8.08 (s, 1H, Ar), 8.18 (s, 1H, Ar); MS: m/e (ES−) 421 (M−1);analysis: C₁₉H₁₉ClN₂O₅S.2H₂O requires C, 49.73, H, 5.05; N, 6.10; Cl,7.73; S, 6.99; found: C, 50.27, H, 5.12; N, 6.12, Cl, 7.47, S, 6.92%.

Example 194-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid mesylate

A solution of methane sulfonic acid (0.058 mL, 0.852 mmol) in methanol(1 mL) was added to a solution of compound of Example 18 (0.3 g, 0.710mmol) in methanol (10 mL) at 25° C. and filtered. The solution wasstirred for 1 h and the precipitated solid was filtered, washed usingmethanol and dried to obtain the title compound. Yield: 0.244 g, (66%);mp 278-280° C.; ¹H NMR (DMSO-d₆, 300 MHz): δ 2.31 (s, 3H, CH₃), 2.62 (s,3H, CH₃), 3.21 (s, 4H, 2CH₂), 3.38 (s, 4H, 2CH₂), 5.16 (s, 2H, CH₂),7.19 (s, 1H, Ar), 7.19 (s, 1H, Ar), 8.06 (s, 1H, Ar), 8.13 (s, 1H, Ar),8.80 (s, 1H, NH); MS: m/e (ES+) 423 (M+1, freebase); analysis:C₂₀H₂₃ClN₂O₈S₂ requires C, 46.29, H, 4.47; N, 5.40, Cl, 6.83, S, 12.36;found: C, 46.75, H, 4.26; N, 5.37, Cl, 7.33, S, 12.58%.

Example 204-Chloro-2-(4-formyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

Sodium formate (0.1 g, 1.37 mmol) was added to a solution of4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester (free base of example 16, 0.3 g, 0.68 mmol) in formicacid (85%, 5 mL), and stirred at 90° C. for 15 h. The reaction mixturewas diluted using water (10 mL), extracted using ethyl acetate, washedwith water and brine. Solvent was removed and the crude product waspurified by column chromatography (silica gel, 1.5% methanol inchloroform) to obtain the title compound. Yield: 0.11 g, (35%); ¹H NMR(DMSO-d₆, 300 MHz): δ 2.62 (s, 3H, CH₃), 3.17-3.24 (m, 4H, 2CH₂), 3.47(s, 4H, 2CH₂), 3.85 (s, 3H, OCH₃), 5.15 (s, 2H, CH₂), 7.13 (s, 1H, Ar),7.17 (s, 1H, Ar), 8.06 (s, 1H, CHO), 8.08 (t, 1H, Ar), 8.14 (d, 1H, Ar);MS: m/e (ES+) 465 (M+1); analysis: C₂₁H₂₁ClN₂O₆S.0.5H₂O requires C,53.23, H, 4.64; N, 5.91, Cl, 7.49, S, 6.75; found: C, 53.82, H, 4.48; N,5.42, Cl, 8.07, S, 7.17%.

Example 212-(4-Acetyl-piperazin-1-yl)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

Acetyl chloride (0.15 mL, 2.06 mmol) was added to a solution of4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester (free base of example 16, 0.3 g, 0.68 mmol) indichloromethane (15 mL) and stirred at 20° C., for 10 min. To this,pyridine (0.33 mL, 4.12 mmol) was added and the mixture was stirredfurther for 18 h. The solvent was removed from the mixture and water (15mL) was added. The pH of the reaction mixture was adjusted to 3 usingaqueous hydrochloric acid (10%). The solid obtained was filtered and thecrude obtained was purified by column chromatography (silica gel, 2%methanol in chloroform) to obtain the title compound. Yield: 0.3 g,(91%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.02 (s, 3H, CH₃), 2.63 (s, 3H,CH₃), 3.15 (s, 2H, CH₂), 3.17 (s, 2H, CH₂), 3.55 (s, 4H, 2CH₂), 3.85,(s, 3H, OCH₃), 5.16 (s, 2H, CH₂), 7.09 (d, 1H, Ar), 7.15 (d, 1H, Ar),8.08 (t, 1H, Ar), 8.15 (t, 1H, Ar); MS: m/e (ES+) 479 (M+1).

Example 224-Chloro-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

To a solution of2-[bis-(2-chloroethyl)amino]-4-chloro-6-methyl10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylicacid [prepared by hydrolysis of compound of Example 12, 0.5 g, 1.044mmol], in methanol (8 mL), aminoethanol (0.25 mL, 4.17 mmol) was addedand heated to 120° C. in a sealed reactor for 4 h. The reaction mixturewas cooled and the solvent was removed under reduced pressure. To theresidue, methanolic HCl (20 mL) was added and refluxed for 3 h. Solventwas removed and the reaction mixture was basified to pH 8 using sodiumcarbonate solution and extracted using ethyl acetate (3×25 mL). Theorganic layer was washed with water and brine solution, concentrated andthe crude product was purified by column chromatography (silica gel, 1%methanol in chloroform) to obtain the title compound. Yield: 0.317 g,(67.13%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.4 (t, 2H, CH₂), 2.48 (s, 4H,2CH₂), 2.63 (s, 3H, CH₃), 3.17 (s, 4H, 2CH₂), 3.41 (t, 2H, CH₂), 3.86(s, 3H, OCH₃), 4.44 (t, 1H, OH), 5.15 (s, 2H, CH₂), 7.04 (s, 1H, Ar),7.12 (s, 1H, Ar), 8.08 (s, 1H, Ar), 8.15 (s, 1H, Ar); MS: m/e (ES+) 481(M+1); analysis: C₂₂H₂₅ClN₂O₆S requires C, 54.94, H, 5.24; N, 5.82, Cl,7.37, S, 6.67; found: C, 54.78, H, 5.34; N, 5.7, Cl, 7.87, S, 6.88%.

Example 232-(4-Benzyl-piperazin-1-yl)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

A mixture of cesium carbonate (0.33 g, 0.82 mmol) and benzyl chloride(0.1 mL, 0.82 mmol) was added to a solution of4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.3 g,0.68 mmol) in DMF (10 mL) and heated at 80° C. for 5 h. Reaction mixturewas concentrated, water (10 mL) was added and the solid filtered. Thecrude obtained was purified by column chromatography (silica gel, 1% to3% methanol in chloroform) to obtain the title compound. Yield: 0.11 g,(30.4%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.62 (s, 3H, CH₃), 3.18 (s, 4H,2CH₂), 3.31 (s, 4H, 2CH₂), 3.50 (s, 2H, CH₂), 3.85 (s, 3H, OCH₃), 5.14(s, 2H, CH₂), 7.04 (s, 1H, Ar), 7.11 (s, 1H, Ar), 7.3-7.32 (m, 5H, Ar),8.08 (s, 1H, Ar), 8.14 (s, 1H, Ar); MS: m/e (ES+) 528 (M+1); analysis:C₂₇H₂₇ClN₂O₅S requires C, 61.53, H, 5.16; N, 5.32, Cl, 6.73, S, 6.08;found: C, 61.22, H, 4.99; N, 4.82, Cl, 6.91, S, 6.15%.

Example 244-Chloro-6-methyl-2-[4-(2-methyl-benzoyl)-piperazin-1-yl]-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

Carbonyl diimidazole (0.074 g 0.55 mmol) was added to a solution of2-toluic acid (0.111 g, 0.67 mmol) in DMF (3 mL) and stirred at 22° C.for 1 h. To this, a solution of4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester (free base of example 16, 0.2 g, 0.45 mmol) in DMF (2mL) was added and stirred at 22° C. for 1 h. Solvent was removed and icewater (5 mL) was added. The solid separated was filtered, washed withwater. The crude product obtained was purified by column chromatography(silica gel, ethyl acetate/pet ether) to obtain the title compound.Yield: 0.093 g (53%); mp: 201-204° C.; ¹H NMR (DMSO-d₆, 500 MHz): δ 2.23(s, 3H, CH₃), 2.64 (s, 3H, CH₃), 3.15 (s, 2H, CH₂), 3.28 (s, 2H, CH₂),3.34 (s, 2H, CH₂), 3.39 (s, 2H, CH₂), 3.87 (s, 3H, OCH₃), 5.16 (s, 2H,CH₂), 7.12 (s, 1H, Ar), 7.16 (s, 1H, Ar), 7.20 (m, 4H, Ar), 8.11 (s, 1H,Ar), 8.16 (s, 1H, Ar); MS: m/e (ES+) 555 (M+1).

Example 254-Chloro-2-(4-methanesulfonyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

Mesyl chloride (0.16 mL, 2.059 mmol) was added to a solution of4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester (free base of example 16, 0.3 g, 0.687 mmol) indichloromethane (20 mL) and stirred at 20° C. for 10 min. To thispyridine (0.3 mL, 4.12 mmol) was added and the reaction mixture wasstirred further for 5 h. The reaction mixture was washed using aqueoushydrochloric acid 10% (15 mL), water and then brine solution. Solventwas removed and the crude product obtained was purified by columnchromatography (silica gel, 1% methanol in chloroform) to obtain thetitle compound. Yield: 0.14 g, (38.45%); ¹H NMR (DMSO-d₆, 300 MHz): δ2.63 (s, 3H, CH₃), 2.90 (s, 3H, CH₃), 3.22 (s, 4H, 2CH₂); 3.31 (s, 4H,CH₂); 3.85 (s, 3H, OCH₃); 5.16 (s, 2H, CH₂), 7.13 (d, 1H, Ar), 7.18 (s,1H, Ar), 8.09 (t, 1H, Ar), 8.15 (d, 1H, Ar); MS: m/e (ES+) 515 (M+1);analysis: C₂₁H₂₃ClN₂O₇S₂.H₂O requires C, 47.32, H, 4.73; N, 5.26, Cl,6.65, S, 12.03; found: C, 46.86, H, 4.18; N, 4.96, Cl, 7.11, S, 12.57%.

Example 264-(4-Chloro-8-methoxycarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-piperazine-1-carboxylicacid benzyl ester

Carbonyl diimidazole (0.34 g, 0.021 mmol) was added to a solution ofbenzyl alcohol (0.2 g, 0.014 mmol) in DMF (3 mL) and stirred at 22° C.for 1 h. To this, a solution of4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester (free base of example 16, 0.228 g, 0.016 mmol) in DMF(2 mL) was added dropwise and stirred at 22° C. for 1 h. Solvent wasremoved and ice water (5 mL) was added. The solid separated wasfiltered, washed with water. Crude was crystallised using ethyl acetateto obtain the title compound. Yield: 0.093 g (53%); mp: 170-173° C.; ¹HNMR (DMSO-d₆, 300 MHz): δ 2.47 (s, 3H, CH₃), 3.25 (s, 4H, 2CH₂), 3.52(s, 4H, 2CH₂), 3.85 (s, 3H, OCH₃), 5.09 (s, 2H, CH₂), 5.15 (s, 2H, CH₂),7.09 (s, 1H, Ar), 7.14 (s, 1H, Ar), 7.32 (m, 5H, Ar), 8.09 (s, 1H, Ar),8.15 (s, 1H, Ar); MS: m/e (ES+) 572 (M+1).

Example 274-Chloro-2-(4-cyclopropyl-2-oxo-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester hydrochloride

Cyclopropyl amine (0.082 g, 14 mmol) was added to a stirred solution ofcompound of Example 27a (0.3 g, 5.9 mmol) in dry dimethylformamide (5mL) under nitrogen atmosphere. The reaction mixture was stirred at 80°C. for 2 h. Solvent was partially removed and the reaction mixture wasdiluted with water (50 mL). Solid separated was filtered, washed withwater and dried. The crude product obtained was purified by columnchromatography (silica gel, 1% methanol/chloroform) and then convertedto its hydrochloride salt using methanolic-HCl to obtain the titlecompound. Yield: 0.18 g (58.06%); mp: 205° C. dec.; ¹H NMR (DMSO-d₆, 300MHz): δ 0.79-0.81 (m, 2H, CH₂), 1.07 (bs, 2H, CH₂), 2.60 (s, 3H, CH₃),2.89 (bs, 1H, CH), 3.65-3.70 (m, 4H, 2CH₂), 3.88 (s, 3H, OCH₃),4.12-4.15 (m, 2H, CH₂), 5.37 (s, 2H, CH₂), 7.61 (s, 1H, Ar), 7.68 (s,1H, Ar), 8.15 (s, 1H, Ar), 8.18 (s, 1H, Ar); MS: m/e (ES+) 490 (M+1,free base).

Example 27a4-Chloro-2-[(2-chloro-acetyl)-(2-chloro-ethyl)-amino]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylicacid methyl ester

4-Chloro-2-(2-chloro-ethylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylicacid methyl ester (prepared by following the method described in example29a or example 29b, 1.9 gm, 4.4 mmol) was added to chloroacetyl chloride(6 mL) at room temperature. Reaction mixture was then stirred at 90° C.for 1 h. Reaction mixture was cooled and diluted using ice water (100mL). The solid separated was filtered, washed with water and dried toobtain the title compound. Yield: 1.85 g, (83%); ¹H NMR (DMSO-d₆, 300MHz): δ 2.60 (s, 3H, CH₃), 3.67 (t, 2H, CH₂), 3.88 (s, 3H, OCH₃), 3.99(t, 2H, CH₂), 4.27 (bs, 2H, CH₂), 5.31 (s, 2H, CH₂), 7.66 (s, 1H, Ar),7.80 (s, 1H, Ar), 8.17 (s, 1H, Ar), 8.19 (s, 1H, Ar); MS: m/e (ES+) 505(M+1).

Example 284-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid isopropyl ester hydrochloride

Concentrated sulphuric acid (1 mL) was added dropwise to a stirredsolution of compound of Example 18 (0.5 g, 1.18 mmol) in dry isopropanol(50 mL) at 90° C. The reaction mixture was stirred at 90° C. for 2 h.Solvent was removed and the residue was taken in chloroform (100 mL) andthis was neutralized using sodium carbonate solution (10%). Chloroformlayer was washed with water, brine and dried over sodium sulphate.Solvent was removed and the product obtained was converted tohydrochloride salt by using isopropanol/ethereal-HCl to obtain the titlecompound. Yield: 0.4 g (67.79%); mp: 262-64° C.; ¹H NMR (DMSO-d₆, 300MHz): δ 1.29 (d, 6H, 2CH₃), 2.63 (s, 3H, CH₃), 3.18 (bs, 4H, 2CH₂), 3.44(bs, 4H, 2CH₂), 5.11 (s, 1H, CH), 5.17 (s, 2H, CH₂), 7.19 (s, 2H, Ar),8.07 (s, 1H, Ar), 8.11 (s, 1H, Ar), 9.45 (bs, 2H, NH, HCl); MS: m/e(ES+) 465 (M+1, free base).

Example 294-Chloro-2-[1,4]diazepan-1yl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl esterhydrochloride

Ammonia solution (25%, 4 mL) was added to a stirred solution of4-chloro-2-[(2-chloro-ethyl)-3-(chloro-propyl)-amino]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid (1.0 g, 2.1 mmol) [obtained by hydrolysis of compound of Example29b] in methanol (10 mL). Reaction mixture was sealed under nitrogenatmosphere and stirred at 110° C. for 6.5 h. Solvent was removed, solidobtained was azeotroped using toluene (20 mL). The residue obtained wassuspended in methanolic-HCl and refluxed overnight (18 h). Solvent wasremoved and chloroform (100 mL) was added. The solution was neutralizedusing sodium carbonate solution (10%). Chloroform layer was washed withwater, brine and dried over sodium sulphate. The crude product obtainedwas purified by column chromatography (silica gel, 4%methanol/chloroform) and then converted to its hydrochloride salt usingmethanolic-HCl to obtain the title compound. Yield: 0.275 g (29.25%);mp: 270° C. dec.; ¹H NMR (DMSO-d₆, 300 MHz): δ 2.06 (bs, 2H, CH₂), 2.63(s, 3H, CH₃), 3.09 (bs, 2H, CH₂), 3.19 (bs, 2H, CH₂), 3.70 (t, 2H, CH₂),3.85 (bs, 2H, CH₂), 3.90 (s, 3H, OCH₃), 5.15 (s, 2H, CH₂), 6.91 (s, 1H,Ar), 6.99 (s, 1H, Ar), 8.08 (s, 1H, Ar), 8.15 (s, 1H, Ar), 9.06 (bs, 1H,NH); MS: m/e (ES+) 451 (M+1, free base).

Example 29a4-Chloro-2-(3-chloropropylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylicacid methyl ester

Powdered sodium-borohydride (0.93 g, 24 mmol) was added in portions at0° C., to a solution of chloropropionic acid (5.32 g, 49 mmol) in THF(13 mL), and benzene (210 mL). Reaction mixture was warmed to roomtemperature and stirred for 1 h, and compound of Example 1 (3.0 g, 8.17mmol) was added. Reaction mixture was refluxed for 3 h. Reaction mixturewas cooled and quenched using sodium bicarbonate solution, and extractedwith ethylacetate. Organic layer was washed with water (100 mL) andbrine (50 mL). The crude product obtained was purified by columnchromatography (silica gel, ethylacetate/pet. ether) to obtain the titlecompound. Yield: 3.7 g (99%); ¹H NMR (DMSO-d₆, 300 MHz): δ 1.96 (q, 2H,CH₂), 2.62 (s, 3H, CH₃), 3.11 (q, 2H, CH₂), 3.72 (t, 2H, CH₂), 3.85 (s,3H, OCH₃), 5.12 (s, 2H, CH₂), 6.29 (s, 1H, Ar), 6.31 (s, 1H, Ar), 8.07(s, 1H, Ar), 8.13 (s, 1H, Ar); MS: m/e (EI) 443 (M+).

Example 29b4-Chloro-2-[(2-chloro-ethyl)(3-chloro-propyl)-amino]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylicacid methyl ester

Powdered sodium-borohydride (0.33 g, 8.6 mmol) was added in portions at0° C., to a solution of chloroacetic acid (1.68 g, 17 mmol) in THF (6mL), and benzene (90 mL). Reaction mixture was warmed to roomtemperature and stirred for 1 h, and compound of Example 29a (1.3 g, 2.9mmol) was added. Reaction mixture was refluxed for 3 h. Reaction mixturewas cooled and quenched using sodium bicarbonate solution, and extractedwith ethylacetate. Organic layer was washed with water (100 mL) andbrine (50 mL). The crude product obtained was purified by columnchromatography (silica gel, ethylacetate/pet-ether) to obtain the titlecompound. Yield: 1.25 g (87%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.00 (t, 2H,CH₂), 2.63 (s, 3H, CH₃), 3.66 (t, 2H, CH₂), 3.69-3.80 (m, 6H, 3×CH₂),3.85 (s, 3H, OCH₃), 5.16 (s, 2H, CH₂), 6.74 (s, 1H, Ar), 6.85 (s, 1H,Ar), 8.08 (s, 1H, Ar), 8.14 (s, 1H, Ar); MS: m/e (EI) 506 (M+).

Example 304-Chloro-6-methyl-2-morpholin-4-yl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

Catalytic amount of p-toluene sulphonic acid (PTSA) was added to astirred solution of compound of Example 13 (1 g, 2.19 mmol) in xylene(50 mL). Reaction mixture was refluxed in Dean-Stark apparatus for 6 hand xylene was removed by distillation. Reaction mixture was dilutedwith 50 mL water, neutralized using 10% sodium bicarbonate solution andextracted using ethyl acetate (3×50 mL), washed with brine (2×10 mL),dried on sodium sulphate. The crude product obtained was purified bycolumn chromatography (silica gel, ethylacetate/pet. ether) to obtainthe title compound. Yield: 0.32 g, (33%); mp: >320° C.; ¹H NMR (DMSO-d₆,300 MHz): δ 2.68 (s, 3H, CH₃), 3.15 (s, 4H, 2CH₂), 3.74 (s, 4H, 2CH₂),3.90 (s, 3H, OCH₃), 4.65 (s, 2H, CH₂), 6.76 (s, 1H, Ar), 6.88 (s, 1H,Ar), 8.06 (s, 1H, Ar), 8.44 (s, 1H, Ar); MS: m/e (EI) 437 (M+).

Example 313-(2-Amino-ethylamino)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester hydrochloride (Compound A) Example 324-Chloro-6-methyl-10,10-dioxo-3-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester hydrochloride (Compound B)

4-Chloro-6-methyl-3-nitro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester is the minor component obtained in the scale up ofExample 1j, which on processing by the methods described in Example 1and Example 12 yielded a mixture of3-(2-chloro-ethyl-amino)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester and3-[bis-(2-chloro-ethyl)-amino]-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester. These esters were hydrolysed to obtain thecorresponding acids.

Aqueous ammonia (2 mL) was added to a stirred solution containing amixture of3-(2-chloro-ethyl-amino)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid and3-[bis-(2-chloro-ethyl)-amino]-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid [(ratio 98:2), 0.7 g, 1.46 mmol)] in methanol (10 mL). Reactionmixture was sealed under nitrogen atmosphere and stirred at 120° C. for6.5 h. Reaction mixture was cooled and the solvent was removed. Solidobtained was azeotroped using toluene and then suspended inmethanolic-HCl (20 mL) and refluxed for 2 h. Solvent was removed and theresidue was suspended in chloroform (50 mL) and neutralized using sodiumcarbonate solution (10%). Chloroform layer was washed with water, brineand dried over sodium sulphate. The crude product obtained was purifiedby column chromatography (silica gel, 2% methanol chloroform) to obtainthe free base of compound A and free base of compound B.

Free base of compound A and free base of compound B were converted tothe hydrochloride salt using methanolic HCl to obtain the title compoundA (Example 31) and title compound B (Example 32).

Compound A

Yield: 0.085 g; mp: 202° C. dec.; ¹H NMR (DMSO-d₆, 300 MHz): δ 2.66 (s,3H, CH₃), 2.99 (bs, 2H, CH₂), 3.39 (bs, 2H, CH₂), 3.86 (s, 3H, OCH₃),5.21 (s, 2H, CH₂), 5.31 (s, 2H, NH₂), 6.66 (d, 1H, Ar), 7.33 (d, 1H,Ar), 7.98 (bs, 2H, NH, HCl), 8.10 (s, 1H, Ar), 8.11 (s, 1H, Ar); MS: m/e(ES+) 411 (M+1, free base).

Compound B

Yield: 0.29 g; mp: 235-37° C.; ¹H NMR (DMSO-d₆, 300 MHz): δ 2.66 (s, 3H,CH₃), 3.08 (bs, 4H, 2CH₂), 3.33 (bs, 4H, 2CH₂), 3.87 (s, 3H, OCH₃), 5.31(s, 2H, CH₂), 7.31 (d, 1H, Ar), 7.64 (d, 1H, Ar), 8.15 (s, 2H, Ar), 9.05(bs, 2H, NH, HCl); MS: m/e (ES+) 437 (M+1); analysis: C₂₀H₂₂Cl₂N₂O₆S.H₂Orequires C, 48.84, H, 4.88; N, 5.69, Cl, 14.44, S, 6.51; found: C,48.94, H, 4.97; N, 5.73, Cl, 14.62, S, 6.63.

Example 33(4-Chloro-6-methyl-10,10-dioxo-2-piperazine-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-8-yl)-aceticacid methyl ester hydrochloride

Aqueous ammonia (5 mL) was added to a stirred solution of{2-[bis-(2-chloro-ethyl)-amino]-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cycloheptene-8-yl}-aceticacid (0.4 g, 0.88 mmol) [obtained by hydrolysis of compound of Example33h] in methanol (20 mL). The reaction mixture was sealed under nitrogenatmosphere and stirred at 120° C. for 6 h. Reaction mixture was cooledand solvent was removed. The residue obtained was azeotroped withtoluene and then suspended in methanolic-HCl (20 mL) and refluxed for 3h and solvent was removed. The residue obtained was suspended inchloroform (50 mL) and neutralized using sodium carbonate solution(10%). Chloroform layer was washed with water, brine and dried oversodium sulphate. The crude product obtained was purified by columnchromatography (silica gel, 2% methanol chloroform) to obtain thecompound, which was converted to the hydrochloride salt using methanolicHCl to obtain the title compound. Yield: 0.23 g (58%); mp: 280° C. dec.;¹H NMR (DMSO-d₆, 300 MHz): δ 2.56 (s, 3H, CH₃), 3.19 (bs, 4H, 2CH₂),3.41 (bs, 4H, 2CH₂), 3.59 (s, 3H, OCH₃), 3.74 (s, 2H, CH₂), 5.06 (s, 2H,CH₂), 7.17 (s, 2H, Ar), 7.43 (s, 1H, Ar), 7.56 (s, 1H, Ar), 9.17 (bs,2H, NH, HCl); MS: m/e (ES+) 451 (M+1). analysis: C₂₁H₂₄Cl₂N₂O₅S requiresC, 51.75, H, 4.96; N, 5.74, C_(1-14.55), S: 6.58; found: C, 51.47, H,4.76; N, 6.04, Cl, 14.96, S, 6.89.

Example 33a4-Chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-8-yl)methanol

Boranedimethylsulphide complex (28 mL, 0.292 mol) was added to a stirredsolution of4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid (19.75 g, 0.058 mol) [obtained by hydrolysis of 11] in dry THF (200mL) under nitrogen atmosphere at 10° C. The reaction mixture was stirredat 60° C. for 3 h. Reaction mixture was cooled and quenched withmethanol, and solvent was removed. The residue was suspended inethylacetate (200 mL) and washed with water, brine and dried over sodiumsulphate. Organic layer was concentrated to obtain the title compound.Yield: 19 g (100%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.60 (s, 3H, CH₃), 4.46(d, 2H, CH₂), 5.17 (s, 2H, CH₂), 5.38 (t, 1H, OH), 7.31 (t, 1H, Ar),7.47 (s, 1H, Ar), 7.55-7.60 (m, 3H, Ar); MS: m/e (EI) 324 (M+).

Example 33b4-Chloro-8-chloromethyl-6-methyl-11-H-5oxa-10-thia.dibenzo-[a,d]cycloheptene-1-10,10-dioxide

Thionyl chloride (80 mL) was added dropwise to a solution of compound ofExample 33a (12 g, 37 mmol). Reaction mixture was stirred at roomtemperature (22° C.) for 2 h. Thionyl chloride was distilled-off and theresidue was suspended in chloroform, washed with water (100 mL), brine(100 mL) and dried over sodium sulphate. Organic layer was concentratedto obtain the title compound. Yield: 11.77 g (93%); ¹H NMR (DMSO-d₆, 300MHz): δ 2.61 (s, 3H, CH₃), 4.79 (s, 2H, CH₂), 5.21 (s, 2H, CH₂), 7.34(t, 1H, Ar), 7.58 (d, 1H, Ar), 7.60 (d, 1H, Ar), 7.64 (s, 1H, Ar), 7.76(s, 1H, Ar); MS: m/e (EI) 342 (M+).

Example 33c4-Chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cyclohepten-8-yl)-acetonitrile

Magnesium sulphate (0.113 g, 0.94 mmol) in water (30 mL) was added to asolution of compound of Example 33b (3.24 g, 9.4 mmol) in DMF (200 mL)followed by addition of sodium cyanide (1.024 g, 20.8 mmol). Reactionmixture was stirred at room temperature (22° C.) overnight (18 h).Reaction was quenched, by adding ferric chloride solution, and DMF wasremoved under vacuum. Residue was suspended in ethyl acetate (100 mL),washed with water (50 mL), brine (50 mL) and dried over sodium sulphate.Organic layer was concentrated to obtain the title compound. Yield: 2.7g (85.44%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.61 (s, 3H, CH₃), 4.08 (s, 2H,CH₂), 5.23 (s, 2H, CH₂), 7.35 (t, 1H, Ar), 7.53-7.60 (m, 3H, Ar), 7.67(s, 1H, Ar); MS: m/e (EI) 333 (M+).

Example 33d4-Chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cyclohepten-8-yl)-aceticacid

Compound of Example 33c (2.5 g, 0.0074 mol) was suspended in mixture ofacetic acid (25 mL) and ortho-phosphoric acid (25 mL). Reaction mixturewas refluxed for 1.5 h, cooled, and neutralized using 10% sodiumbicarbonate solution and extracted with ethyl acetate. Aqueous layer wasacidified using dilute HCl and extracted with ethyl acetate. The organiclayer was washed with water (50 mL), brine (50 mL) and dried over sodiumsulphate. The crude product obtained was purified by columnchromatography (silica gel, methanol-chloroform) to obtain the titlecompound. Yield: 1.98 g, (75.57%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.58 (s,3H, CH₃), 3.63 (s, 2H, CH₂), 5.11 (s, 2H, CH₂), 7.32-7.60 (m, 5H, Ar);MS: m/e (EI) 352 (M+).

Example 33e4-Chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cyclohepten-8-yl)-aceticacid methyl ester

Concentrated sulphuric acid (0.66 mL) was added to a stirred solution ofcompound of Example 33d in dry methanol (100 mL) at reflux temperature.Reaction was refluxed for 6 h. Solvent was removed and the crude wassuspended in ethyl acetate. The organic layer was washed with 10%sodium-bicarbonate solution (50 mL), water (100 mL) and dried oversodium sulphate. The crude product obtained was purified by columnchromatography (silica gel, methanol-chloroform) to obtain the titlecompound. Yield: 3.5 g, (67.43%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.56 (s,3H, CH₃), 3.56 (s, 3H, OCH₃), 3.70 (s, 2H, CH₂), 5.10 (s, 2H, CH₂), 7.32(t, 1H, Ar), 7.48 (s, 1H, Ar), 7.51-7.57 (m, 3H, Ar); MS: m/e (EI) 366(M+).

Example 33f(4-Chloro-6-methyl-2-nitro-10,10-dioxo-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cyclohepten-8-yl)-aceticacid

Cooled sulphuric acid (6 mL) was added to a solution of compound ofExample 33e (2 g, 5.4 mmol) in concentrated nitric acid (30 mL) at 0° C.Reaction mixture was warmed to room temperature (22° C.) and stirred for1.5 h. The reaction mixture was slowly poured into cold water (100 mL),extracted with ethyl acetate. The organic layer was washed with water(50 mL) and dried over sodium sulphate. Organic layer was concentratedto obtain the title compound. Yield: 1.62 g, (72.32%); ¹H NMR (DMSO-d₆,300 MHz): δ 2.57 (s, 3H, CH₃), 3.66 (s, 2H, CH₂), 5.39 (s, 2H, CH₂),7.38 (s, 1H, Ar), 7.52 (s, 1H, Ar), 8.47 (s, 1H, Ar), 8.50 (s, 1H, Ar);MS: m/e (EI) 397 (M+).

Example 33g(2-Amino-4-chloro-6-methyl-10,10-dioxol-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cyclohepten-8-yl)-aceticacid methyl ester

Activated Raney-Nickel (1.6 g) was added to a solution of(4-chloro-6-methyl-2-nitro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-5-aza-dibenzo[a,d]-cyclohepten-8-yl)aceticacid methyl ester (1 g) in DMF (50 mL) [obtained by esterification ofcompound of Example 33f]. Reaction mixture was kept for hydrogenation at45 psi for 3 h. Catalyst was removed by filtering over a bed of celite,washed with DMF and concentrated to reduce the volume to half. Reactionmixture was diluted with water, and the solid obtained was filtered,washed with water and dried to obtain the title compound. Yield: 0.4 g(67.79%); mp. 262-64° C.; ¹H NMR (DMSO-d₆, 300 MHz): δ 2.54 (s, 3H,CH₃), 3.58 (s, 3H, OCH₃), 3.73 (s, 2H, CH₂), 5.03 (s, 2H, CH₂), 6.7-6.8(m, 2H, Ar), 7.5-7.6 (m, 2H, Ar); MS: m/e (ES+) 381 (M+1).

Example 33h{2-[Bis-(2-chloro-ethyl)-amino]-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-8-yl}-aceticacid methyl ester

Powdered sodium borohydride (0.258 g, 7.1 mmol) was added portionwise toa stirred solution of chloroacetic acid (1.37 g, 14 mmol) in benzene (20mL) and THF (2.5 mL) at 0° C. under nitrogen atmosphere. Reactionmixture was warmed to room temperature (22° C.) and stirred for 1.5 h.To this, compound of Example 33g (0.5 g, 1.19 mmol) was added. Reactionmixture was refluxed for 3.5 h, cooled and quenched with 10% sodiumbicarbonate solution and was extracted using ethylacetate (2×100 mL).The organic layer was washed with water (100 mL), brine (50 mL) anddried over sodium sulphate. The crude product obtained was purified bycolumn chromatography (silica gel, pet ether-chloroform) to obtain thetitle compound. Yield: 0.46 g (76.66%); ¹H NMR (CDCl₃, 300 MHz): δ 2.63(s, 3H, CH₃), 3.58 (s, 2H, CH₂), 3.68 (s, 3H, OCH₃), 3.61-3.65 (m, 8H,4×CH₂), 4.64 (s, 2H, CH₂), 6.52 (s, 1H, Ar), 6.66 (s, 1H, Ar), 7.34 (s,1H, Ar), 7.61 (s, 1H, Ar); MS: m/e (ES+) 508 (M+1).

Example 34[4-Chloro-2-(4-ethyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-8-yl]-methanol

Boranedimethylsulphide complex (0.85 mL, 8.7 mmol) was added at 10° C.to a stirred solution of2-(4-acetyl-piperazin-1-yl)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid (0.8 g, 1.7 mmol) [obtained by hydrolysis of compound of Example21] in dry THF (70 mL) under nitrogen atmosphere. The reaction mixturewas stirred at 60° C. for 2 h. Reaction mixture was cooled and quenchedwith methanol and the solvent was removed. Solid was suspended inethylacetate (100 mL) and washed with water, brine and dried over sodiumsulphate. The crude product obtained was purified by columnchromatography (silica gel, 2% methanol-chloroform) to obtain the titlecompound. Yield: 0.5 g (67.74%); mp: 230-32° C.; ¹H NMR (DMSO-d₆, 300MHz): δ 1.88 (t, 3H, CH₃), 2.57 (s, 3H, CH₃), 2.86 (t, 2H, CH₂),2.88-2.91 (m, 4H, 2CH₂), 3.31-3.41 (m, 4H, 2CH₂), 4.45 (d, 2H, CH₂),5.04 (s, 2H, CH₂), 5.37 (t, 1H, OH), 7.07 (s, 1H, Ar), 7.13 (s, 1H, Ar),7.43 (s, 1H, Ar), 7.58 (s, 1H, Ar); MS: m/e (ES+) 437 (M+1).

Example 354-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbaldehyde

DMSO (2.6 mL, 37.5 mmol) was added at −70° C. to a solution of oxalylchloride (0.46 mL, 37.5 mmol) in dichloromethane (10 mL). Reactionmixture was stirred for 5 minutes and to this(4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cyclohepten-8-yl)-methanol(0.489 g, 1.19 mmol) [obtained by following the procedure described inExample 34] in dichloromethane (5 mL) was added. Reaction mixture wasstirred for 5 minutes and to this triethylamine (8.4 mL, 62.5 mmol) wasadded. Reaction mixture was warmed to room temperature (22° C.) andstirred for 0.5 h. the reaction mixture was diluted with dichloromethane(200 mL), washed with water (100 mL), brine (50 mL) and dried oversodium sulphate. The crude product obtained was purified by columnchromatography (silica gel, ethylacetate-pet ether) to obtain the titlecompound. Yield: 0.2 g (42%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.64 (s, 3H,CH₃), 3.20 (s, 4H, 2CH₂), 3.20 (s, 4H, 2CH₂), 5.15 (s, 2H, CH₂), 7.14(d, 2H, Ar), 8.03 (s, 1H, Ar), 8.24 (s, 1H, Ar), 9.97 (s, 1H, CHO); MS:m/e (EI) 406 (M+).

Example 364-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid cyclopropylamide hydrochloride

1,1′-Carbonyldiimidazole (0.172 g, 11 mmol) was added at 25° C., to astirred solution of compound of Example 18 (0.3 g, 7 mmol) in dry DMF(10 mL) under nitrogen atmosphere. The reaction mixture was stirred for2 h, and cyclopropyl amine (0.06 mL, 8.4 mmol) was added. The reactionmixture was stirred at 25° C. for 2 h. Solvent was partially removed andthe reaction mixture was diluted with water (50 mL), The solid separatedwas filtered, washed with water and dried. The product was converted toits hydrochloride salt using methanolic-HCl to obtain the titlecompound. Yield: 0.15 g (42.5%); ¹H NMR (DMSO-d₆, 300 MHz): δ 0.56 (s,2H, CH₂), 0.66 (d, 2H, CH₂), 2.61 (s, 3H, CH₃), 2.82 (bs, 1H, CH),3.20-3.36 (m, 8H, 4-CH₂), 5.11 (s, 2H, CH₂), 7.14 (d, 1H, Ar), 7.66 (d,1H, Ar), 8.01 (s, 1H, Ar), 8.13 (s, 1H, Ar), 8.67 (s, 1H, NH); MS: m/e(ES+) 462 (M+1, freebase).

Example 372-Amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a,d]-cycloheptene-8-carboxylicacid methylester

Activated Raney-Nickel (0.06 g) was added to a solution of compound ofExample 37f (0.3 g, 0.75 mmol) in DMF (50 mL). The reaction mixture wassubjected to hydrogenation (30 psi pressure) for 1 h. Catalyst wasfiltered-off, washed with dimethylformamide and concentrated to reducethe volume to half. The reaction mixture was diluted with water, solidobtained was filtered, washed with water and dried under vacuum toobtain the title compound. Yield: 0.176 g, (63%); mp: 278-280° C.; ¹HNMR (DMSO-d₆, 300 MHz): δ 2.60 (s, 3H, CH₃), 3.90 (s, 3H, OCH₃), 4.80(s, 2H, CH₂), 5.60 (s, 1H, NH), 6.70 (s, 1H, Ar), 6.75 (s, 1H, Ar), 7.50(s, 1H, NH), 7.95 (s, 1H, Ar), 8.30 (s, 1H, Ar); MS: m/e (EI) 366 (M+).analysis: C₁₆H₁₅ClN₂O₄S requires C, 52.39, H, 4.12; N, 7.64, Cl, 9.67,S, 8.75; C, 52.29, H, 4.17; N, 7.07, Cl, 9.92, S, 9.02%.

Example 37a 1-Bromomethyl-3-chloro-2-nitrobenzene

N-Bromosuccinimide (4.67 g, 26.23 mmol) was added to a stirred solutionof 6-methyl-2-chloro-1-nitrobenzene (4.5 g, 26.23 mmol) in distilledcarbon-tetrachloride. Benzoyl peroxide (0.01 g) was added to thereaction mixture and the mixture was refluxed for 8 h. The solidseparated was filtered. The filtrate was concentrated to get the crudeproduct, which was purified by using column chromatography (silica gel,pet.ether 60-80° C.) to obtain the title compound. Yield: 2.69 g, (41%);MS: m/e (CI) 253 (M+1).

Example 37b 4-Bromo-3-(3-chloro-2-nitro-benzylsulfanyl)-5-methyl-benzoicacid methyl ester

Triethylamine (1.16 mL, 8.61 mmol) was added to a stirred solution ofcompound of Example 37a (2.87 g, 11.78 mmol) and compound of Example 1f(1.5 g, 5.74 mmol) in dry dichloromethane (75 mL). The reaction mixturewas stirred at 0° C. for 20 min, was poured in water (100 mL) andextracted with chloroform (2×50 mL). The combined extract was washedwith water (50 mL), brine (50 mL) and concentrated under vacuum toobtain the crude product, which was purified by column chromatography(silica gel, 5% ethyl acetate in pet ether 60-80° C.) to obtain thetitle compound. Yield: 1.93 g, (77.82%); ¹H NMR (DMSO-d₆, 300 MHz): δ2.55 (s, 3H, CH₃), 3.90 (s, 3H, OCH₃), 4.25 (s, 2H, CH₂), 7.45 (s, 1H,Ar), 7.50-7.60 (m, 2H, Ar), 7.75 (s, 1H, Ar), 7.85 (s, 1H, Ar); MS: m/e(ES−) 431 (M−1).

Example 37c4-Bromo-3-(3-chloro-2-nitro-phenylmethanesulfonyl)-5-methylbenzoic acidmethyl ester

Metachloroperbenzoic acid (0.9 g, 5.6 mmol) was added in portions to astirred solution of compound of Example 37b (0.484 g, 1.12 mmol) indichloromethane (50 mL). The reaction mixture was stirred at 25° C. for2 h and was concentrated to remove the solvent. The semisolid obtainedwas stirred with 10% sodium bicarbonate solution (100 mL). The solidobtained was filtered, washed with water (100 mL). The crude productobtained was purified by column chromatography (silica gel, 15% ethylacetate in pet ether 60-80° C.) to obtain the title compound). Yield:0.48 g, (92.30%); ¹H NMR (DMSO-d₆, 300 MHz): δ 2.65 (s, 3H, CH₃), 3.95(s, 3H, OCH₃), 5.15 (s, 2H, CH₂), 7.60 (d, 1H, Ar), 7.70 (t, 1H, Ar),7.95 (s, 1H, Ar), 8.20 (s, 1H, Ar), 8.35 (s, 1H, Ar); MS: m/e (ES+) 463(M+1).

Example 37d 3-(2-Amino-3-chloro-phenylmethanesulfonyl)-4-bromo-5-methylbenzoic acid methyl ester

Activated Raney-Nickel was added to a solution of compound of Example37c (1.50 g, 3.46 mmol) in dimethylformamide (100 mL). The reactionmixture was subjected to hydrogenation (25 psi pressure) for 2 h.Catalyst was filtered-off, washed with dimethylformamide andconcentrated to obtain the crude product, which was then purified bycolumn chromatography (silica gel, 30% ethyl acetate in pet. ether60-80° C.) to obtain the title compound. Yield: 0.785 g, (56.07%). MS:m/e (ES+) 433 (M+1).

Example 37e4-Chloro-6-methyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a,d]-cycloheptene-8-carboxylicacid methylester

Sodium hydride (0.234 g, 5.07 mmol) was added in portions to a stirredsolution of Example 37d (0.785 g, 1.69 mmol) in dry dimethylformamide(10 mL) at 0° C. The reaction mixture was stirred for 0.5 h. Excesssodium hydride was destroyed using methanol (5 mL). The reaction mixturewas diluted with cold water (100 mL), the solid separated was filtered,crystallized using ethyl acetate/pet. ether 60-80° C. to obtain thetitle compound. Yield: 0.409 g, (64.10%); ¹H NMR (DMSO-d₆, 300 MHz): δ2.65 (s, 3H, CH₃), 3.90 (s, 3H, OCH₃), 5.15 (s, 2H, CH₂), 7.25 (t, 1H,Ar), 7.65 (d, 1H, Ar), 7.75 (d, 1H, Ar), 7.85 (s, 1H, NH), 8.05 (s, 1H,Ar), 8.35 (s, 1H, Ar); MS: m/e (EI) 351 (M+).

Example 37f4-Chloro-6-methyl-2-nitro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a,d]-cycloheptene-8-carboxylicacid methylester

Cooled sulfuric acid (1 mL) was added to a solution of compound ofExample 37e (0.3 g, 0.85 mmol) in concentrated nitric acid (10 mL) at 0°C. The reaction mixture was stirred at 0° C. for 1.5 h. The reactionmixture was slowly poured in cold water (100 mL), solid obtained wasfiltered, washed with water till pH was neutral. Solid obtained wascrystallized using ethyl acetate/pet. ether 60-80° C. to obtain thetitle compound. Yield: 0.31 g, (91.70%); ¹H NMR (DMSO-d₆, 300 MHz): δ2.70 (s, 3H, CH₃), 3.90 (s, 3H, OCH₃), 5.30 (s, 2H, CH₂), 8.10 (s, 1H,Ar), 8.15 (s, 1H, Ar), 8.35 (s, 1H, NH), 8.55 (s, 2H, Ar); MS: m/e (EI)396 (M+).

Example 384-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5H-10-lambda*6*-thia-5-aza-dibenzo[a,d]-cycloheptene-8-carboxylicacid methyl ester

Sodium formate (0.074 g, 0.108 mmol) was added to a suspension ofcompound of Example 37 (0.20 g, 0.547 mmol) in formic acid (2 mL) andrefluxed for 1.5 h. The reaction mixture was cooled and poured into icewater (50 mL). The solid precipitated was filtered, washed with waterand dried. The crude product was purified by trituration withchloroform/methanol (3:1) to obtain the title compound. Yield: 0.18 g(84%); mp: 280-282° C.; ¹H NMR (DMSO-d₆, 300 MHz): δ 2.48 (s, 3H, CH₃),3.82 (s, 3H, OCH₃), 4.91 (s, 2H, CH₂, trans minor isomer), 4.97 (s, 2H,CH₂, cis major isomer), 7.30 (d, 1H, Ar, trans minor isomer), 7.47 (d,1H, Ar, trans minor isomer), 7.56 (s, 1H, Ar, cis major isomer), 7.63(s, 1H, Ar, cis major isomer), 7.89 (s, 1H, Ar), 7.94 (s, 1H, Ar), 8.26(s, 1H, CHO, cis major isomer), 8.29 (s, 1H, NH), 8.78 (d, 1H, CHO,trans minor isomer), 10.40 (d, 1H, NH, trans minor isomer), 10.46 (s,1H, NH, cis major isomer); MS: m/e (ES+) 395 (M+1); analysis:C₁₇H₁₄ClNO₆S requires C, 51.72H, 3.83; N, 7.10, Cl, 8.98, S, 8.12; foundC, 51.24, H, 3.80; N, 6.79, Cl, 9.22, S, 7.84%.

Example 395-10,10-Trioxo-10,11-dihydro-5H-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

Metachloroperbenzoic acid (1.96 g, 11.4 mmol) was added to a solution ofcompound of Example 39a (0.65 g, 2.28 mmol) in dichloromethane (20 mL)in two portions at 0° C. and the reaction mixture stirred at 25° C. for2 h. The reaction mixture was concentrated, treated with sodiumbicarbonate solution (50 mL) and extracted with ethyl acetate. Thecombined organic layer was washed with water, brine, dried, concentratedand purified using flash chromatography (silica gel, 1% methanol inchloroform) to obtain the title compound. Yield: 0.6 g (83%); ¹H NMR(CDCl₃, 300 MHz): δ 4.00 (s, 3H, CH₃), 4.82 (s, 2H, CH₂), 7.29 (t, 1H,Ar), 7.59 (m, 1H, Ar), 7.85 (d, 1H, Ar), 8.02 (d, 1H, Ar), 8.10 (d, 1H,Ar), 8.35 (d, 1H, Ar), 8.71 (s, 1H, Ar); MS: m/e (EI) 316 (M+).

Example 39a5-oxo-5,11-dihydro-10-thia-dibenzo[a,d]cycloheptene-8-carboxylic acidmethyl ester

The title compound was obtained using the reported procedure (J. Med.Chem., 21, 10, 1035, (1978)). Yield: 55%; ¹H NMR (CDCl₃, 300 MHz): δ3.93 (s, 3H, OCH₃), 4.08 (s, 2H, CH₂), 7.27 (d, 1H, Ar), 7.36 (t, 1H,Ar), 7.49 (t, 1H, Ar), 7.6 (d, 1H, Ar), 7.85 (d, 1H, Ar), 8.00 (s, 1H,Ar), 8.23 (s, 1H, Ar); MS: m/e (EI) 284 (M+).

Example 405-Hydroxy-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester

Platinum oxide (0.015 g, 10% w/w) was added to a solution of compound ofExample 39 (0.15 g, 0.47 mmol) in ethanol (50 mL) and acetic acid (20mL). The reaction mixture was subjected to hydrogenation at 100 psi ofhydrogen at 65° C. for 11 h. It was cooled to 30° C. and filteredthrough high flow bed. The mixture was concentrated, diluted with waterand extracted with ethyl acetate. The combined organic layer was washedwith 10% sodium bicarbonate solution (15 ml), water, brine, concentratedand crystallized with ethyl acetate/pet. ether 60-80° C. to obtain thetitle compound. Yield: 125 mg (82%); ¹H NMR (DMSO-d₆, 300 MHz): δ 3.87(s, 3H, OCH₃), 5.23 (d, 1H, CH_(a)), 5.53 (d, 1H, CH_(a′)), 6.49 (d, 1H,CH_(b)), 6.49 (d, 1H, CH_(b′)), 7.33 (m, 2H, Ar), 7.48 (d, 1H, Ar), 7.57(d, 1H, Ar), 8.00 (d, 1H, Ar), 8.17 (d, 1H, Ar), 8.25 (s, 1H, Ar); MS:m/e (CI) 319 (M+1).

Example 4110,10-Dioxo-10,11-dihydro-5H-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester

Pd/C (0.015 g, 10% w/w) and catalytic amount of perchloric acid wasadded to a solution of compound of Example 40 (0.11 g, 0.3 mmol) inacetic acid (60 mL). The reaction mixture was subjected to hydrogenationat 100 psi of hydrogen at 65° C. for 6.5 h. The reaction mixture wascooled to 25° C. and filtered through high flow bed. The filtrate wasconcentrated, diluted with water and extracted with ethyl acetate. Thecombined organic layer was washed with water, brine, concentrated andpurified using flash chromatography (silica gel, ethyl acetate and pet.ether 60-80° C.) to obtain the title compound. Yield: 0.05 g (47%); ¹HNMR (CDCl₃, 300 MHz): δ 3.90 (s, 3H, OCH₃), 4.32 (s, 2H, CH₂), 5.21 (s,2H, CH₂) 7.38 (m, 5H, Ar), 8.09 (d, 1H, Ar), 8.61 (s, 1H, Ar); MS: m/e(CI) 303 (M+1).

The efficacy of the present compounds in inhibiting the activity ofTNF-α can be determined by a number of pharmacological assays well knownin the art and described below. The exemplified pharmacological assays,which follow, have been carried out with the compounds of the presentinvention and their salts.

In Vitro Screening to Identify Inhibitors of TNF-α Example 42 PrimaryScreening Whole Blood Cell Culture Assay

TNF-α production by lipopolysaccharide (LPS) in whole blood was measuredaccording to the method described by Wilson et al (J. Immunol. Methods,139: 233-240, 1991). Briefly, blood was collected from healthy donorsinto potassium EDTA vacutainer tubes (Vacutest Plast/Becton Dickinson)and diluted with RPMI 1640 culture medium (Gibco BRL, Pasley, UK)containing 100 U/ml penicillin and 100 μg/ml streptomycin, (100×solution, Sigma Chemical Co. St Louis, Mo.) with no added serum. Thewhite blood cell count was adjusted to 1×10⁶ cells/ml and 100 μl/well ofthe diluted blood was transferred into 96-well culture plates. Followingcell plating, 79 μl of culture medium and 1 μl of the test compounds(final concentration 1 μM) dissolved in DMSO (dimethylsulfoxide, Sigma,Mo., USA) was added to the cells. The final concentration of DMSO wasadjusted to 0.5%. 1 μl of vehicle (0.5% DMSO) was used as control.Rolipram (100 μM) was used as a standard compound. The plates wereincubated for 30 min at 37° C. in an atmosphere of 5% CO₂. Finally, 20μl (10 μg/ml) per well of LPS (Escherchia coli 0127:B8, Sigma ChemicalCo., St. Louis, Mo.) was added, for a final concentration of 1 μg/ml.Plates were incubated at 37° C. for 4.5 h in an atmosphere of 5% CO₂.Supernatants were harvested and assayed for TNF-α by ELISA as describedby the manufacturer (R&D Systems, MN) or by cytotoxicity bioassay inL929 cells. Percent inhibition of TNF-α release in comparison to thecontrol was calculated.

The results are indicated in Table 1.

TABLE 1 % inhibition of Example No. TNF-α release 06 89 09 31 11 51 1641 24 74 26 85 28 70 29 76 31 66 32 96 33 95 35 45 37 33 38 45

The results indicate that the compounds of the present invention haveinhibitory effects against TNF-α release.

Example 43 Secondary Screening Peripheral Blood Mononuclear Cells(PBMCS)

TNF-α production by LPS in peripheral blood mononuclear cells (PBMC) wasmeasured according to the method described by Henry et al (J. Bioorg.Med. Chem. Lett., 8: 3335-3340, 1998). Briefly, blood was collected fromhealthy donors into Potassium EDTA vacutainer tubes (VacutestPlast/Becton Dickinson). PBMC were isolated using gradientcentrifugation in Ficoll-Paque solution (Pharmacia). Isolated PBMC weresuspended in RPMI 1640 culture medium (Gibco BRL, Pasley, UK) containing10% fetal bovine serum (FBS) (Hyclone, Utah, USA), 100 U/ml penicillin(Sigma Chemical Co. St Louis, Mo.) and 100 μg/ml streptomycin (SigmaChemical Co. St Louis, Mo.). The cell concentration was adjusted to1×10⁶ cells/ml. The viability as determined by trypan blue dye exclusionwas uniformly ≧98%. The cell suspension (100 μl) was added to the wellsof a 96-well culture plate. Following cell plating, 79 μl of the culturemedium and 1 μl of eight different concentrations of the test compounds(final concentration 0.03, 0.1, 0.3, 1, 3, 10, 30, 100 μM) dissolved inDMSO (dimethylsulfoxide, Sigma, Mo., USA) were added to the cells. Thefinal concentration of DMSO was adjusted to 0.5%. The appropriate DMSOconcentration was used as control. Rolipram (30 μM) was used as astandard compound. The plates were incubated for 30 min at 37° C. in anatmosphere of 5% CO₂. Finally, 20 μl (10 μg/ml) per well of LPS,(Escherchia coli 0127:B8, Sigma Chemical Co., St. Louis, Mo.) was added,for a final concentration of 1 μg/ml. The plates were incubated at 37°C. for 4.5 h in an atmosphere of 5% CO₂. To determine the cytotoxicityof the test compounds, the cell viability was assessed using MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfonyl)-2H-tetrazolium)reagent (Promega) after 4.5 h of incubation. Supernatants were harvestedand assayed for TNF-α by ELISA as described by the manufacturer (R&DSystems, MN, BD Biosciences Pharmingen) or by cytotoxicity bioassay inL929 cells. The 50% inhibitory concentration (IC₅₀) values werecalculated by a nonlinear regression method using GraphPad software(Prism 3.03)

The results are indicated in Table 2.

TABLE 2 Example No. IC₅₀ (μM) % toxicity (10 μM), 5 h 01 8.60 12 5A 8.60± 1.30 00 5B 9.10 ± 1.6  00 09 2.60 09 11 21.00  25 15 0.55 25 16 0.1862 17 0.10 66 20 1.10 24 21 4.00 44 22 0.88 16 24 3.87 ± 1.42 03 25 0.6018 26 8.05 ± 1.57 00 28 10.50  15 29 0.51 ± 1.58 23 31 0.84 21 32 0.1627 33 0.20 29 35 1.40 07 38 1.20 ± 1.58 10 ± 04 40 >10.00   8

The results indicate that the compounds of the present invention haveinhibitory effects against TNF-α release with minimal toxicity.

Example 44 Effect on Proinflammatory Cytokines Produced by SynovialCells Obtained from a Rheumatoid Arthritis (RA) Patient

Cytokine production by synovial cells obtained from a rheumatoidarthritis (RA) patient undergoing knee replacement surgery was measuredaccording to the method described by Brennan, F. M. et al (The Lancet.July 29: 244-247, 1989). The synovial membrane tissue was digested inDMEM (Gibco) containing 10% FBS, 100 U/ml penicillin and 100 μg/mlstreptomycin, 4 mg/ml collagenase type I (Worthington), 1.5 μg/ml Dnasetype I (Sigma) and 15 U/ml heparin and incubated at 37° C. for 3 hours.After incubation, the digested tissue was filtered through a 70-μmembrane and the cells washed 3 times in complete medium (DMEM with 10%FBS). The synovial cells were cultured at 1×10⁶ cells/ml inpresence/absence of the test compound for 10 hours. The supernatantswere harvested by centrifugation and levels of the cytokines (TNF-α,IL-1β, and IL-6) measured by ELISA. To assess the cytotoxic effect ofthe test compound, the cellular viability test was performed using MTSreagent.

Results: Compounds of the present invention were found to inhibitproinflammatory cytokines (TNF-α, IL-1β, and IL-6) produced by synovialcells obtained from a RA patient.

Example 45 Effect on Proinflammatory Cytokines Released byLPS-Stimulated hPBMCS

The effect of the active molecules on the proinflammatory cytokines;interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukin-8 (IL-8)was measured using the supernatants generated in the primary screeningassay [as described in Example 42]. The levels of these cytokines wereestimated by ELISA as described by the manufacturer. (OptiEIA ELISAsets, BD Biosciences, Pharmingen). The 50% inhibitory concentration(IC₅₀) values were calculated by a nonlinear regression method usingGraphPad software (Prism 3.03).

Results: Compounds of the present invention were found to inhibitproinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6)and interleukin-8 (IL-8) released by LPS-stimulated hPBMCs.

In Vivo Studies Example 46 Lipopolysaccharide (LPS)-Induced TumorNecrosis Factor (TNF)-α Release in BALB/c Mice

The protocol described by Fukuda T. et al (Eur. J. Pharmacol., 391:317-320, 2000) was followed. BALB/c mice were divided into groups offive to ten each. The test compound, suspended in Tween 80-0.5% carboxymethylcellulose (CMC), with a few drops of Tween 80 as wetting agent ifnecessary, was administered orally (p.o.) to the mice. One hour later,LPS dissolved in sterile, pyrogen-free saline was administered i.p. atthe dose of 1 mg/kg. The negative control group received saline as ani.p injection, while all other groups received LPS. Rolipram (30 mg/kg)was used as the standard drug. One and a half hours later, blood wascollected in heparin. Plasma was separated by centrifugation at 13000rpm (Heraeus Biofuge Pico Centrifuge) at room temperature, aliquoted andstored at −70° C. until analysis.

TNF-α levels in the blood samples were assayed using ELISA and %inhibition of TNF-α release compared to the control group wascalculated.

The results are indicated in Table 4.

TABLE 4 Example No. Dose (mg/kg, po) % inhibition (Mean ± SE*) n** 1 1064.86 ± 3.97 5 3 100  40.72 ± 12.66 6 7 100 55.84 ± 9.24 5 11 100 77.87± 9.85 5 16 100 72.19 ± 3.17 10 18 100 22.66 ± 8.47 10 20 30  27.87 ±17.52 5 21 30 54.56 ± 11.7 5 22 100 57.66 ± 5.66 10 24 30 17.56 ± 8.7210 25 30  33.57 ± 16.46 5 26 100 68.68 ± 3.68 10 29 100 79.08 ± 0.91 10*standard error **number of BALB/c mice used in the experiment

The results indicate that the compounds of the present invention exhibitgood in vitro and in vivo TNF-α inhibitory activity.

1. A method of inhibiting TNF-α activity in a mammal in need thereofcomprising administering to said mammal a therapeutically effectiveamount of a compound of formula (1a)

wherein R₁, R₂, R₃, R₄, R₅, R₆ and R₈ are each independently selectedfrom: hydrogen, halogen, hydroxy, alkyl, alkenyl, cycloalkyl, alkoxy,cyano, nitro, trifluoromethyl, aryl, heterocyclyl, heteroaryl,alkylsulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl,—S(O)₂—NH-heterocyclyl, —S(O)₂—NH-heteroaryl, sulfonamide,—S(O)₂—NH-alkyl, —S(O)₂—NH-cycloalkyl, —S(O)₂—NH-aryl, —NH—S(O)₂-alkyl,—NH—S(O)₂-cycloalkyl, —NH—S(O)₂-aryl, —NH—S(O)₂-heterocyclyl,—NH—S(O)₂-heteroaryl, NR₁₁R₁₂, hydrazine and N═R′; R₇ is alkyl,—(CH₂)_(n)C(O)R₉ or —C(O)NR₁₁R₁₂; R₉ is hydrogen, halogen, alkyl,cycloalkyl, trifluoromethyl, OR₁₀, aryl or heterocyclyl; R₁₀ ishydrogen, alkyl, cycloalkyl, trifluoromethyl, aryl or heterocyclyl; R₁₁and R₁₂ are each independently selected from: hydrogen, alkyl,cycloalkyl, alkylamino, aryl, heteroaryl, heterocyclyl, —(CH₂)_(n)C(O)R₉and cycloalkylaminoalkylcarbonyl; or R₁₁ and R₁₂, together with the Natom to which they are bonded, form a 5-, 6-, 7- or 8-memberedheterocyclyl, optionally having one or more additional heteroatomsselected from: O, N and S; R′ is heterocyclyl or cycloalkyl; n is 0, 1or 2; where alkyl or cycloalkyl is unsubstituted or substituted by oneor two of the same or different groups selected from: halogen, hydroxy,alkylcarboxy, amino, cycloalkyl, alkoxy, aryloxy, alkoxylcarbonyl,arylalkoxycarbonyl, aminocarbonyl, alkylamino, dialkylamino,cycloalkylamino, cycloalkyl alkylamino, heterocyclyl alkylamino,heteroarylamino, heteroarylalkylamino, aryl, amino aryl, heteroaryl andheterocyclyl; heterocyclyl is unsubstituted or substituted by one or twoof the same or different groups selected from: halogen, hydroxy, alkoxy,oxo, alkyl, cycloalkyl, cycloalkyl alkyl, aryl, hydroxyalkyl, amino,aminoalkyl, alkylaminoalkyl, heterocyclyl alkyl, heteroaryl alkyl,aralkyl, alkylheteroaryl, cycloalkylheteroaryl, formyl, alkylcarbonyl,alkoxycarbonyl, aryl alkoxycarbonyl, cycloalkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, —SH, —S-alkyl, —S(O)₂-alkyl, —S(O)₂-aryl, alkylaminoand alkylheteroarylamino; aryl is unsubstituted or substituted by one ortwo of the same or different groups selected from: halogen, nitro,alkyl, trifluoromethyl, alkoxy, amino, mono- or di-alkylamino,heteroaryl alkyl and aralkyl; heteroaryl is unsubstituted or substitutedby one or two of the same or different groups selected from: halogen,alkyl, cycloalkyl, nitro and amino; W is S(O)_(m); and m is 1 or 2; inall its stereoisomeric and tautomeric forms and mixtures thereof in allratios, and its pharmaceutically acceptable salts and solvates.
 2. Amethod of inhibiting TNF-α activity in a mammal in need thereofcomprising administering to said mammal a therapeutically effectiveamount of a compound of formula (1a)

wherein R₁ is hydrogen, C₁-C₄ alkyl or halogen; R₂ is hydrogen, halogen,amino, nitro, cyano, heterocyclyl, heterocyclyl C₁-C₄alkylheterocyclyl,aminoC₁-C₄ alkylheterocyclyl, aryl C₁-C₄ alkylheterocyclyl,heteroarylbenzyl C₁-C₄ alkylheterocyclyl, heteroaryl C₁-C₄alkylheterocyclyl, di(C₁-C₄ alkyl)benzylheterocyclyl, C₃-C₆cycloalkylheterocyclyl, C₃-C₆cycloalkyl heteroaryl,heteroarylcarbonylheterocyclyl, heterocyclylsulfonyl,—S(O)₂—NH-heterocyclyl, C₁-C₄ alkylsulfonyl, C₁-C₄ alkoxy, C₃-C₆cycloalkylC₁-C₄alkyl, —NR₁₁R₁₂, NHR₁₆ or N=heterocyclyl; R₃ is hydrogen,NR₁₁R₁₂ or NHR₁₆; R₄ and R₅ are each independently selected from:hydrogen, halogen, C₁-C₄ alkyl, nitro, amino, haloC₁-C₄alkylamino andheterocyclyl C₁-C₄ alkylamino; R₆ and R₅ are each independently selectedfrom: hydrogen, C₁-C₄ alkyl and halogen; R₇ is hydroxy C₁-C₄ alkyl,chloro C₁-C₄ alkyl, cyano C₁-C₄ alkyl, formyl, —(CH₂)_(n)C(O)OR₁₀ orCONHR₁₆; R₁₀ is hydrogen, C₁-C₄ alkyl, amino C₁-C₄ alkyl, heterocyclylC₁-C₄ alkyl, aryl, heteroaryl or heterocyclyl; R₁₁ and R₁₂ are eachindependently selected from: hydrogen, C₁-C₄ alkyl, hydroxy C₁-C₄ alkyl,haloC₁-C₄ alkyl, aminoC₁-C₄ alkyl, arylC₁-C₄ alkyl,C₃-C₆cycloalkylC₁-C₄alkyl, C₆-C₁₀ aryl, heterocyclyl or heteroaryl; orR₁₁ and R₁₂, together with the N atom to which they are bonded, form a6- or 7-membered heterocyclyl, optionally having one or more additionalN or O heteroatoms; R₁₆ is formyl, C₁-C₄ alkyl, C₃-C₆cycloalkyl,heterocyclylC₁-C₄alkyl, heteroaryl C₁-C₄alkyl, heteroarylamino C₁-C₄alkyl, di (C₁-C₄)alkyl amino C₁-C₄ alkyl, amino C₁-C₄ alkyl,heterocyclyl C₁-C₄alkylamino C₁-C₄ alkyl, halo C₁-C₄ alkyl, di(C₁-C₄)alkyl amino C₁-C₄ alkyl amino C₁-C₄alkyl, carboxy (C₁-C₄)alkyl,hydroxy C₁-C₄ alkyl, trifluoromethylcarbonyl, di (C₁-C₄alkyl)aminoC₁-C₄alkylcarbonyl, C₃-C₆ cycloalkylaminoC₁-C₄alkylcarbonyl, haloC₁-C₄alkylcarbonyl, hydroxy C₁-C₄ alkylcarbonyl, C₁-C₄ alkylcarbonyl,C₁-C₄ alkyl aminoC₁-C₄alkylcarbonyl, C₆-C₁₀ aryl carbonyl,benzyloxycarbonyl, halo carbonyl C₁-C₄alkylcarbonyl, amino carbonylC₁-C₄alkylcarbonyl, C₁-C₄alkoxycarbonyl C₁-C₄alkylcarbonyl,C₁-C₄alkylcarbonyloxy C₁-C₄alkylcarbonyl or heterocyclyl C₁-C₄alkylcarbonyl; n is 0, 1 or 2; where heterocyclyl is unsubstituted orsubstituted by one or two of the same or different groups selected from:halogen, hydroxy, C₁-C₄ alkoxy, oxo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,C₃-C₆ cycloalkyl C₁-C₄ alkyl, C₆-C₁₀ aryl, hydroxy C₁-C₄ alkyl, amino,amino C₁-C₄ alkyl, C₁-C₄ alkylamino C₁-C₄ alkyl, heterocyclyl C₁-C₄alkyl, heteroaryl C₁-C₄alkyl, C₆-C₁₀ aryl C₁-C₄ alkyl, C₁-C₄alkylheteroaryl, C₃-C₁₀ cycloalkylheteroaryl, formyl,C₁-C₄alkylcarbonyl, C₁-C₄ alkoxycarbonyl, C₆-C₁₀ aryl C₁-C₄alkoxycarbonyl, C₆-C₁₀ arylcarbonyl, C₃-C₁₀ cycloalkylcarbonyl,heteroarylcarbonyl, —SH, —S—C₁-C₄ alkyl, —S(O)₂—C₁-C₄ alkyl,—S(O)₂—C₆-C₁₀ aryl, C₁-C₄ alkylamino and C₁-C₄ alkylheteroarylamino;aryl is unsubstituted or substituted by one or two of the same ordifferent groups selected from: halogen, nitro, C₁-C₄alkyl,trifluoromethyl, C₁-C₄ alkoxy, amino, mono- or di-C₁-C₄ alkylamino,heteroaryl C₁-C₄ alkyl and C₆-C₁₀arC₁-C₄ alkyl; and heteroaryl isunsubstituted or substituted by one or two of the same or differentgroups selected from: halogen, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, nitro andamino; W is S(O)_(m); and m is 1 or 2; in all its stereoisomeric andtautomeric forms and mixtures thereof in all ratios, and itspharmaceutically acceptable salts and solvates.
 3. The method accordingto claim 1, wherein R₂ is hydrogen, halogen, nitro, amino, cyano,C₁-C₄alkyl, C₁-C₄alkoxy, morpholinyl, 1,4-diazepanyl,4-cyclopropyl-2-oxo-piperazinyl, piperazinyl, N-formyl piperazinyl,C₁-C₄ alkylcarbonyl piperazinyl, C₁-C₄alkyl piperazinyl, hydroxyC₁-C₄alkyl piperazinyl, C₁-C₄alkyl sulfonyl piperazinyl, C₃-C₆cycloalkyl piperazinyl, benzyl piperazinyl, C₁-C₄ alkoxycarbonylpiperazinyl, C₆-C₁₀ aryl C₁-C₄ alkoxycarbonyl piperazinyl, C₆-C₁₀arylcarbonyl piperazinyl, aminoC₁-C₄alkyl piperazinyl, substitutedphenyl C₁-C₄alkyl piperazinyl, imidazolylbenzyl C₁-C₄alkyl piperazinyl,C₃-C₆cycloalkylthiadiazolylpiperazinyl, pyrrolylcarbonylpiperazinyl,furanylC₁-C₄ alkylpiperazinyl, dimethylaminobenzylpiperazinyl,thiophenylC₁-C₄ alkylpiperazinyl, morpholinylC₁-C₄alkyl piperazinyl,C₁-C₄alkyl sulfonyl, piperazinylsulfonyl, isooxazolylaminosulfonyl,formyl amino, C₁-C₄ alkylamino, dimethyl amino, C₁-C₄alkylcarbonylamino, dimethylamino C₁-C₄alkylcarbonylamino, C₃-C₆cycloalkylaminoC₁-C₄alkylcarbonyl amino, hydroxyC₁-C₄alkylcarbonylamino, C₁-C₄alkylcarbonyloxy C₁-C₄alkylcarbonylamino,chloro C₁-C₄alkylcarbonylamino, morpholinyl C₁-C₄ alkylcarbonylamino,trifluoromethylcarbonylamino, benzyloxycarbonylamino,piperazinylC₁-C₄alkylamino, phenylalkylamino, imidazolylamino C₁-C₄alkyl amino, imidazolyl C₁-C₄ alkyl amino, dimethylamino C₁-C₄alkylamino, isobutylamino, amino C₁-C₄ alkylamino, morpholinylC₁-C₄alkylamino C₁-C₄ alkylamino, morpholinyl C₁-C₄ alkylamino, C₃-C₆cycloalkylC₁-C₄alkylamino, chloro C₁-C₄alkylamino, dimethylaminoC₁-C₄alkylamino C₁-C₄ alkylamino, carboxy C₁-C₄ alkylamino, hydroxy C₁-C₄alkylamino, di(hydroxy C₁-C₄ alkyl)amino, di(chloroC₁-C₄alkyl)amino,benzyloxycarbonylC₁-C₄alkylamino, NR₁₁R₁₂ or pyrrolidin-2ylidene; R₁₁and R₁₂ are each independently selected from: hydrogen, C₁-C₄ alkyl,morpholinyl C₁-C₄alkyl, C₆-C₁₀ aryl C₁-C₄ alkyl,C₃-C₆cycloalkylC₁-C₄alkyl, hydroxy C₁-C₄ alkyl, chloro C₁-C₄alkyl,C₆-C₁₀ aryl, heterocyclyl and heteroaryl; where heterocyclyl issubstituted with C₁-C₄ alkyl; and aryl is substituted with one or two ofthe same or different groups selected from: halogen, trifluoromethyl,C₁-C₄ alkyl, C₁-C₄ alkoxy and mono- or di-substituted amino; R₃ ishydrogen, amino, C₁-C₄alkylamino, amino C₁-C₄alkylamino, unsubstitutedpiperazinyl or piperazinyl substituted by C₁-C₄alkyl; R₄ is hydrogen orhalogen; R₅ is hydrogen or C₁-C₄ alkyl; and R₇ is C(O)OC₁-C₄ alkyl,C(O)OH, CH₂C(O)OC₁-C₄ alkyl, CH₂C(O)OH, formyl, hydroxy C₁-C₄ alkyl,chloro C₁-C₄ alkyl, cyano C₁-C₄ alkyl or —C(O)NH C₃-C₆ cycloalkyl; W isS(O)_(m); and m is 1 or
 2. 4. The method according to claim 3, whereinR₂ is amino, formylamino, C₁-C₄alkylamino, C₁-C₄alkylcarbonylamino,chloro C₁-C₄alkylcarbonylamino, hydroxy C₁-C₄alkylcarbonylamino,C₁-C₄alkylcarbonyloxyC₁-C₄alkylcarbonylamino, carboxyC₁-C₄alkylamino,di(chloroC₁-C₄alkyl)amino, di(hydroxyC₁-C₄alkyl)amino, acetamide,propionamide, morpholinyl, [1,4]diazepanyl, unsubstituted piperazinyl orpiperazinyl substituted by at least one group selected from: C₁-C₄alkyl,C₃-C₆cycloalkyl, formyl, C₁-C₄alkylcarbonyl, hydroxy C₁-C₄alkyl,C₁-C₄alkylsulfonyl, benzyl, oxo, C₁-C₄ alkoxycarbonyl,benzyloxycarbonyl, unsubstituted C₆-C₁₀ arylcarbonyl or C₆-C₁₀arylcarbonyl substituted by at least one group selected from:C₁-C₄alkyl, C₁-C₄alkoxy, halogen and trifluoromethyl; R₃ is hydrogen; R₄is halogen; R₅ is C₁-C₄ alkyl; and R₇ is C(O)OC₁-C₄ alkyl, C(O)OH,CH₂C(O)OC₁-C₄ alkyl or CH₂C(O)OH_(i) W is S(O)_(m); and m is 1 or
 2. 5.The method according to claim 4, wherein R₁ and R₂ are hydrogen; R₃ isamino, amino C₁-C₄alkylamino, unsubstituted piperazinyl or piperazinylsubstituted by C₁-C₄alkyl; R₄ is chloro, bromo or fluoro; R₅ is methylor ethyl; R₆ and R₈ are hydrogen; and R₇ is C(O)OC₁-C₄ alkyl, or C(O)OH.6. The method according to claim 3, wherein R₁ is hydrogen; R₂ isunsubstituted piperazinyl or piperazinyl substituted by C₁-C₄alkyl,C₃-C₆cycloalkyl, formyl, C₁-C₄ alkylcarbonyl, hydroxy C₁-C₄alkyl,C₁-C₄alkylsulfonyl, benzyl, oxo, C₁-C₄ alkoxycarbonyl,benzyloxycarbonyl, unsubstituted C₆-C₁₀ arylcarbonyl or C₆-C₁₀arylcarbonyl substituted by C₁-C₄alkyl; R₃ is hydrogen; R₄ is chloro,bromo or fluoro; R₅ is methyl or ethyl; and R₆ and R₈ are hydrogen. 7.The method according to claim 1, wherein Win the compound of formula(1a) is SO₂.
 8. The method according to claim 1, wherein the compound offormula (1a) is selected from the group consisting of:2-Amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester;2-Amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid;2-Amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid sodium salt;4-Chloro-2-(2-chloro-acetylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester;4-Chloro-2-(2-hydroxy-acetylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester;2-(2-Acetoxy-acetylamino)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester;4-Chloro-6-methyl-10,10-dioxo-2-propionylamino-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester;4-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid;4-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid sodium salt;4-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester;-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid ethyl ester;4-Chloro-2-formylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid isopropyl ester;2-[Bis-(2-chloro-ethyl)amino]-4-chloro-6-methyl10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylicacid methyl ester;2-[Bis-(2-hydroxy-ethyl)amino]-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester;4-Chloro-6-methyl-2-piperazin-1-yl-11H-5-oxa-10-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester hydrochloride;4-Chloro-6-methyl-10-oxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*4*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester hydrochloride;4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylic acid methyl esterhydrochloride;4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl estermesylate;4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid;4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid mesylate;4-Chloro-2-(4-formyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester;2-(4-Acetyl-piperazin-1-yl)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester;4-Chloro-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester;2-(4-Benzyl-piperazin-1-yl)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester;4-Chloro-6-methyl-2-[4-(2-methyl-benzoyl)-piperazin-1-yl]-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester;4-Chloro-2-(4-methanesulfonyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester;4-(4-Chloro-8-methoxycarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-piperazine-1-carboxylicacid benzyl ester;4-Chloro-2-(4-cyclopropyl-2-oxo-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester hydrochloride;4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid isopropyl ester;4-Chloro-2-[1,4]diazepan-1yl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester hydrochloride;4-Chloro-6-methyl-2-morpholin-4-yl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester;3-(2-Amino-ethylamino)-4-Chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid methyl ester hydrochloride;4-Chloro-6-methyl-10,10-dioxo-3-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl esterhydrochloride; (4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl,10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-yl)aceticacid methyl ester hydrochloride;4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbaldehyde;[4-Chloro-2-(4-ethyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-yl]-methanol;or4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylicacid cyclopropyl amide hydrochloride.
 9. A method for the treatment ofdisorders associated with abnormal TNF-αactivity in mammals comprisingadministering a compound of the formula (1a) according to claim 1 or itstautomer, stereoisomer, pharmaceutically acceptable salt, orpharmaceutically acceptable solvate thereof.
 10. A method according toclaim 9, wherein the disorder associated with abnormal TNF-α activity isselected from a group comprising of: inflammatory bowel disease,inflammation, rheumatoid arthritis, juvenile rheumatoid arthritis,psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis,chronic non-rheumatoid arthritis, osteoporosis/bone resorption, Crohn'sdisease, septic shock, endotoxic shock, atherosclerosis,ischemia-reperfusion injury, coronary heart disease, vasculitis,amyloidosis, multiple sclerosis, sepsis, chronic recurrent uveitis,hepatitis C virus infection, malaria, ulcerative colitis, cachexia,psoriasis, plasmocytoma, endometriosis, Behcet's disease, Wegerer'sgranulomatosis, meningitis, AIDS, HIV infection, autoimmune disease,immune deficiency, common variable immunodeficiency (CVID), chronicgraft-versus-host disease, trauma and transplant rejection, adultrespiratory distress syndrome, pulmonary fibrosis, recurrent ovariancancer, lymphoproliferative disease, refractory multiple myeloma,myeloproliferative disorder, diabetes, juvenile diabetes, ankylosingspondylitis, skin delayed type hypersensitivity disorders, Alzheimer'sdisease, systemic lupus erythematosus and allergic asthma.
 11. A methodfor the treatment of inflammatory conditions associated with abnormalTNF-α activity in mammals comprising administering a compound of formula(1a) according to claim 1, or its tautomer, stereoisomer,pharmaceutically acceptable salt, pharmaceutically acceptable solvatethereof.
 12. A method according to claim 11, wherein the inflammatorycondition is selected from the group consisting of inflammatory boweldisease, inflammation, rheumatoid arthritis, juvenile rheumatoidarthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoidarthritis, chronic non-rheumatoid arthritis, Crohn's disease,osteoporosis/bone resorption or allergic asthma.